NO315516B1 - Triazolo-pyridazine derivatives as ligands for GABA receptors - Google Patents

Description

Foreliggende oppfinnelse angår en klasse av substituerte triazolo-pyridazinderivater og deres anvendelse innen terapi. Nærmere bestemt angår oppfinnelsen substituerte 1,2,4-triazolo[4,3-b]pyridazinderivater som er ligander for GABAA-reseptorer og er derfor anvendbare ved terapi av ødeleggende, mentale tilstander. The present invention relates to a class of substituted triazolo-pyridazine derivatives and their use in therapy. More specifically, the invention relates to substituted 1,2,4-triazolo[4,3-b]pyridazine derivatives which are ligands for GABAA receptors and are therefore useful in the therapy of devastating mental conditions.

Reseptorer for den hovedinhiberende neurotransmitter, gamma-aminosmørsyre (GABA), er oppdelt i to hovedklasser: (1) GABAA-reseptorer, som er medlemmer av den ligåndstyrte ione-kanalsuperfamilie; og (2) GABAB-reseptorer, som kan være medlemmer av den G-proteinkjedede reseptorsuperfamilie. Etter at de første cDNA som kodet individuelle GABAA-reseptorsubenheter, ble klonet, har antallet av kjente medlemmer av pattedyrfami-lien vokst til å innbefatte minst seks a-subenheter, fire p-subenheter, tre y-subenheter, én 5-subenheter, én e-subenhet og to p-subenheter. Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two major classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAB receptors, which may be members of the G protein-coupled receptor superfamily. After the first cDNAs encoding individual GABAA receptor subunits were cloned, the number of known members of the mammalian family has grown to include at least six α-subunits, four β-subunits, three γ-subunits, one 5-subunit, one e-subunit and two p-subunits.

Selv om kjennskap til diversiteten av GABAA-reseptor-genfamilien representerer et stort skritt fremover i vår for-ståelse av denne ligåndstyrte ionekanal, er innsikt innen graden av subtypediversitet fremdeles et tidlig trinn. Det er blitt indikert at en a-subenhet, en p-subenhet og en y-subenhet utgjør det minimale krav for å danne en fullt ut funksjonell GABAA-reseptor uttrykt ved forbigående transfeksjon av cDNA i celler. Som ovenfor angitt eksisterer også 5-, e- og p-subenheter, men er bare til stede i en mindre grad i GABAA-reseptor-populasj oner. Although knowledge of the diversity of the GABAA receptor gene family represents a major step forward in our understanding of this ligand-gated ion channel, insight into the degree of subtype diversity is still an early step. It has been indicated that an α-subunit, a β-subunit and a γ-subunit constitute the minimal requirement to form a fully functional GABAA receptor expressed by transient transfection of cDNA into cells. As indicated above, 5-, ε- and β-subunits also exist, but are only present to a lesser extent in GABAA receptor populations.

Studier over reseptorstørrelse og visualisering ved elektronmikroskopi konkluderer med, som andre medlemmer av den ligåndstyrte ionekanalfamilie, at den naturlige GABAA-reseptor eksisterer i pentamer form. Valget av minst én a-, én p- og én y-subenhet fra et repertoar av 17, muliggjør en eventuell eksi-stens på mer enn 10 000 pantamere subenhetkombinasjoner. Enn videre tar denne beregning ikke i betraktning de ytterligere permutasjoner som ville være mulig hvis arrangementet av subenheter rundt ionekanalen ikke hadde noen begrensninger (dvs. det kunne være 120 mulige varianter for en reseptor sammensatt av fem forskjellige subenheter). Studies of receptor size and visualization by electron microscopy conclude, like other members of the ligand-gated ion channel family, that the natural GABAA receptor exists in pentameric form. The selection of at least one a, one p and one y subunit from a repertoire of 17 enables the eventual existence of more than 10,000 pantameric subunit combinations. Furthermore, this calculation does not take into account the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (ie, there could be 120 possible variants for a receptor composed of five different subunits).

Reseptorsubtypesammensetninger som ikke eksisterer, innbefatter blant mange andre, ctlp2y2, Ct2p2/3y2, ct3|3y2/3, a2pyl, oc5P3y2/3, a6Py2, a6p8 og a4p5. Subtypesammensetninger inneholdende en al-subenhet, er til stede i de fleste områder av hjer-nen og er antatt å utgjøre over 40 % av GABAA-reseptorer i rotter. Subtypesammensetninger inneholdende oc2- og a3-subenheter, er antatt å utgjøre ca. 25 % og 17 % av GABAA-reseptorer i rotter. Subtypesammensetninger inneholdende en a5-subenhet, ut-trykkes hovedsakelig i hippocampus og korteks, og er antatt å representere ca. 4 % av GABAA-reseptorene i rotter. Receptor subtype compositions that do not exist include, among many others, ctlp2y2, Ct2p2/3y2, ct3|3y2/3, a2pyl, oc5P3y2/3, a6Py2, a6p8, and a4p5. Subtype compositions containing an α1 subunit are present in most areas of the brain and are thought to make up over 40% of GABAA receptors in rats. Subtype compositions containing oc2 and a3 subunits are thought to amount to approx. 25% and 17% of GABAA receptors in rats. Subtype compositions containing an a5 subunit are expressed mainly in the hippocampus and cortex, and are thought to represent approx. 4% of GABAA receptors in rats.

En karakteristisk egenskap av alle kjente GABAA-reseptorer er nærvær av et antall modulerende seter, hvor ett er det benzodiazepin(BZ)-bindende sete. BZ-bindingssetet er det mest undersøkte av de GABAA-reseptormodulerende seter, og er det setet gjennom hvilket anxiolytiske legemidler, slik som diazepam og temazepam, utøver deres effekt. Før kloning av GABAA-reseptorgenfamilien ble det benzodiazepinbindende setet historisk oppdelt i to subtyper, BZl og BZ2, på basis av radioligandbindingsstudier. BZl-subtypen er blitt vist å være farmakologisk ekvivalent med en GABAA-reseptor omfattende al-subenheten i kombinasjon med en p-subenhet og y2. Denne er den mest rikelige GABAA-reseptor sub type, og er antatt å representere praktisk talt halvparten av alle GABAA-reseptorer i hj ernen. A characteristic feature of all known GABAA receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine (BZ)-binding site. The BZ binding site is the most studied of the GABAA receptor modulating sites, and is the site through which anxiolytic drugs, such as diazepam and temazepam, exert their effects. Prior to cloning of the GABAA receptor gene family, the benzodiazepine binding site was historically divided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies. The BZ1 subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the α1 subunit in combination with a β subunit and γ2. This is the most abundant GABAA receptor subtype, and is thought to represent practically half of all GABAA receptors in the brain.

To andre hovedpopul as joner er <x2py2 og oc3Py2/3-sub-typene. Sammen utgjør disse tilnærmet ytterligere 35 % av det totale GABAA-reseptorrepertoar. Farmakologisk synes denne kom-binasjonen å være ekvivalent med BZ2-subtypen, som definert tidligere ved radioligandbinding, selv om BZ2-subtypen også kan innbefatte visse a5-holdige subtypesammensetninger. Den fysiologiske rolle av disse subtyper har hittil vært uklar fordi ingen tilstrekkelig selektive agonister eller antagonister har vært kjent. Two other main populations are the <x2py2 and oc3Py2/3 subtypes. Together, these make up approximately a further 35% of the total GABAA receptor repertoire. Pharmacologically, this combination appears to be equivalent to the BZ2 subtype, as defined previously by radioligand binding, although the BZ2 subtype may also include certain α5-containing subtype compositions. The physiological role of these subtypes has so far been unclear because no sufficiently selective agonists or antagonists have been known.

Det er nå antatt at midler som virker som BZ-agonister ved aiPy2-, a2Py2- eller a3py2-subenhetene, vil utvise ønskelige anxiolytiske egenskaper. Forbindelser som er modulatorer av det benzodiazepinbindende setet av GABAA-reseptoren ved å virke som BZ-agonister, er heretter angitt som "GABAA-reseptor-agonister". De a-selektive GABAA-reseptoragonister, alpidem og zolpidem, er klinisk foreskrevet som hypnotiske midler, hvilket antyder at i det minste noe av den sedasjon som er assosi-ert med kjente anxiolytiske midler som virker ved BZ1-bindingssetet, er formidlet via GABAA-reseptorer inneholdende otl-subenheten. Følgelig tas det i betraktning at GABAA-reseptor-agonister som interagerer mer fordelaktig med <x2- og/eller <x3-subenheten enn med al, vil være effektive ved behandling av angst med en redusert sannsynlighet for å forårsake sedasjon. Midler som er antagonister eller inverse agonister ved al, vil også kunne anvendes for å reversere sedasjon eller hypnose forårsaket av al-agonister. It is now believed that agents acting as BZ agonists at the aiPy2, a2Py2 or a3py2 subunits will exhibit desirable anxiolytic properties. Compounds which are modulators of the benzodiazepine binding site of the GABAA receptor by acting as BZ agonists are hereinafter referred to as "GABAA receptor agonists". The α-selective GABAA receptor agonists, alpidem and zolpidem, are clinically prescribed as hypnotics, suggesting that at least some of the sedation associated with known anxiolytic agents acting at the BZ1 binding site is mediated via GABAA receptors containing the ot1 subunit. Accordingly, it is contemplated that GABAA receptor agonists that interact more favorably with the <x2 and/or <x3 subunit than with α1 would be effective in the treatment of anxiety with a reduced likelihood of causing sedation. Agents that are antagonists or inverse agonists at al, will also be able to be used to reverse sedation or hypnosis caused by al agonists.

Forbindelsene ifølge foreliggende oppfinnelse som er selektive ligander for 6ABAA-reseptorer, kan derfor anvendes ved behandling og/eller forhindring av et utall sykdommer på sentralnervesystemet. Slike sykdommer innbefatter angstsykdom-mer, slik som panisk sykdom med eller uten agorafobi, agorafobi uten noen panikksykdomshistorie, dyre- og andre fobier innbefattende sosiale fobier, obsessiv-kompulsiv sykdom, stressykdommer, innbefattende posttraumatisk og akutt stress-sykdom, og generaliserte eller substansfremkalte angstsykdom-mer; neuroser, konvulsjoner; migrene, depressive eller bipol-are sykdommer, f.eks. enkel-episode eller vedvarende stor dep-ressiv sykdom, dystymisk sykdom, maniske sykdommer av bipolar I- og bipolar II-type, og syklotymisk sykdom; psykotiske sykdommer innbefatter schizofreni; neurodegenerering som oppstår fra cerebral ischemi; oppmerksomhetssvikt-hyperaktiv!tets-syndrom; og forstyrrelser på døgnrytmen, f.eks. i personer som lider av effekten av jetlegg eller skiftarbeide. The compounds according to the present invention, which are selective ligands for 6ABAA receptors, can therefore be used in the treatment and/or prevention of numerous diseases of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without any history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders, including post-traumatic stress disorder and acute stress disorder, and generalized or substance-induced anxiety disorder -more; neuroses, convulsions; migraine, depressive or bipolar diseases, e.g. single-episode or persistent major depressive disorder, dysthymic disorder, bipolar I and bipolar II type manic disorders, and cyclothymic disorder; psychotic illnesses include schizophrenia; neurodegeneration arising from cerebral ischemia; attention deficit hyperactivity disorder; and disturbances in the circadian rhythm, e.g. in people suffering from the effects of jet lag or shift work.

Ytterligere sykdommer for hvilke selektive ligander for GABAA-reseptorer kan være gunstig, innbefatter smerte og nocisepsjon; emesis, innbefatter akutt, forsinket og anticipa-torisk emesis, i særdeleshet emesis fremkalt av kjemoterapi eller bestråling, så vel som postoperativ kvalme og brekning-er; spiseforstyrrelser innbefattende anoreksi nervosa og buli-mi nervosa; premenstruelt syndrom; muskelspasmer eller spasti-sitet, f.eks. i paraplegiske pasienter; og hørselstap. Selektive ligander for GABAA-reseptorer kan også være effektive som premedikamentering før anestesi eller mindre prosedyrer, slik som endoskopi, innbefattende gastrisk endoskopi. Additional diseases for which selective ligands for GABAA receptors may be beneficial include pain and nociception; emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as postoperative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasms or spasticity, e.g. in paraplegic patients; and hearing loss. Selective ligands for GABAA receptors may also be effective as premedication before anesthesia or minor procedures, such as endoscopy, including gastric endoscopy.

I DE-A-2741763 og US-patentskrifter 4 260 755, In DE-A-2741763 and US Patent Nos. 4,260,755,

4 260 756 og 4 654 343 er det beskrevet forskjellige klasser av 1,2,4-triazolo[4,3-b]pyridazinderivater som er angitt å være anvendbare som anxiolytiske midler. Forbindelsene beskrevet i DE-A-2741763 og i US-patentskrifter 4 260 755 og 4 654 343, utviser en fenylsubstituent ved 6-stillingen av triazolopyridazinringsystemet. Forbindelsene beskrevet i US-patentskrift 4 260 756, utviser en heteroarylgruppe ved 6-eller 8-stillingen. I ingen av disse publikasjoner er det imidlertid noen beskrivelse eller forslag på 1,2,4-triazolo-[4,3-b]pyridazinderivater hvori substituenten ved 6-stillingen er bundet via et direkte kjedet oksygenatom. 4,260,756 and 4,654,343 there are described various classes of 1,2,4-triazolo[4,3-b]pyridazine derivatives which are indicated to be useful as anxiolytic agents. The compounds described in DE-A-2741763 and in US Patents 4,260,755 and 4,654,343 exhibit a phenyl substituent at the 6-position of the triazolopyridazine ring system. The compounds described in US Patent 4,260,756 exhibit a heteroaryl group at the 6- or 8-position. In none of these publications, however, is there any description or suggestion of 1,2,4-triazolo-[4,3-b]pyridazine derivatives in which the substituent at the 6-position is bound via a directly chained oxygen atom.

EP-A-0085840 og EP-A-0134946 beskriver beslektede serier av 1,2,4-triazolo[3,4-a]ftalazinderivater som er angitt å utvise antiangstaktivitet. Det finnes imidlertid ingen beskrivelse eller noe forslag i noen av disse publikasjoner på å erstatte benzogruppen av triazolo-ftalazinringsystemet med noen annen funksjonalitet. EP-A-0085840 and EP-A-0134946 describe related series of 1,2,4-triazolo[3,4-a]phthalazine derivatives which are reported to exhibit antianxiety activity. However, there is no description or suggestion in any of these publications to replace the benzo group of the triazolo-phthalazine ring system with any other functionality.

Foreliggende oppfinnelse tilveiebringer en klasse av triazolo-pyridazinderivater som utviser ønskelige bindende egenskaper til forskjellige GABAA-reseptorsubtyper. Forbindelsene ifølge foreliggende oppfinnelse har god affinitet som ligander for a.2- og/eller a3-subenheten av den humane GABAA-reseptor. Forbindelsene ifølge oppfinnelsen kan interagere mer fordelaktig med <x2- og/eller oc3-subenheten enn med al-subenheten. Fordelaktig vil forbindelsene ifølge oppfinnelsen utøve funksjonell selektivitet i form av selektiv virksomhet for a2- og/eller a3-subenheten i forhold til al-subenheten. The present invention provides a class of triazolo-pyridazine derivatives that exhibit desirable binding properties to various GABAA receptor subtypes. The compounds according to the present invention have good affinity as ligands for the α2 and/or α3 subunit of the human GABAA receptor. The compounds according to the invention may interact more advantageously with the <x2 and/or oc3 subunit than with the α1 subunit. Advantageously, the compounds according to the invention will exercise functional selectivity in the form of selective activity for the a2 and/or a3 subunit in relation to the a1 subunit.

Forbindelsene ifølge foreliggende oppfinnelse er GABAA-reseptorsubtypeligander som har en bindende affinitet (Ki) for a2- og/eller a3-subenheten, som målt i den utprøvning som er beskrevet senere, på 100 nM eller mindre, typisk 50 nM eller mindre og ideelt på 10 nM eller mindre. Forbindelsene ifølge foreliggende oppfinnelse kan utvise minst 2-dobbel, hensiktsmessig minst 5-dobbel, og fortrinnsvis minst 10-dobbel selektiv affinitet for a2- og/eller a3-subenheten i forhold til al-subenheten. Imidlertid er forbindelser som ikke er selektive uttrykt ved deres bindende affinitet for a2- og/eller a3-subenheten i forhold til al-subenheten, også omfattet innen oppfinnelsens ramme, i det slike forbindelser fordelaktig vil utøve funksjonell selektivitet uttrykt ved en selektiv virksomhet overfor tx2- og/eller a3-subenheten i forhold til ccl-subenheten. Enn videre utviser forbindelsene ifølge foreliggende oppfinnelse interessante farmakokinetiske egenskaper, i særdeleshet uttrykt ved forbedret oral biotilgjengelighet. The compounds of the present invention are GABAA receptor subtype ligands that have a binding affinity (Ki) for the α2 and/or α3 subunit, as measured in the assay described below, of 100 nM or less, typically 50 nM or less and ideally of 10 nM or less. The compounds according to the present invention can exhibit at least 2-fold, suitably at least 5-fold, and preferably at least 10-fold selective affinity for the α2 and/or α3 subunit in relation to the α1 subunit. However, compounds that are not selective expressed by their binding affinity for the α2 and/or α3 subunit in relation to the α1 subunit are also encompassed within the scope of the invention, in that such compounds will advantageously exercise functional selectivity expressed by a selective activity towards tx2 - and/or the a3 subunit in relation to the ccl subunit. Furthermore, the compounds according to the present invention exhibit interesting pharmacokinetic properties, in particular expressed by improved oral bioavailability.

Foreliggende oppfinnelse tilveiebringer en forbindelse av formel I eller et farmasøytisk akseptabelt salt derav: The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

hvori in which

Z betegner trifluormetyl, 2-metylpropyl, 2,2-dimetyl-propyl, 3-metylbutyl, 1-fluorbut-3-enyl, syklobutyl, 1-metylsyklobutyl, 1-fluorsyklobutyl, 3-fluorsyklobutyl, 3,3-difluorsyklobutyl, 3-hydroksysyklobutyl, 3-benzyloksysyklobutyl, 3-oksosyklobutyl, 1-metylsykloheksyl, 4,4-difluor-l-metylsykloheksyl, syklopentylmetyl, 4-fluorsykloheks-3-enyl, 3-fluorfenyl, tetrahydrofur-2-yl, pyrrolidin-l-yl, 4-metyltetrahydropyran-4-yl eller tien-2-yl, Z denotes trifluoromethyl, 2-methylpropyl, 2,2-dimethyl-propyl, 3-methylbutyl, 1-fluorobut-3-enyl, cyclobutyl, 1-methylcyclobutyl, 1-fluorocyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 3- hydroxycyclobutyl, 3-benzyloxycyclobutyl, 3-oxocyclobutyl, 1-methylcyclohexyl, 4,4-difluoro-l-methylcyclohexyl, cyclopentylmethyl, 4-fluorocyclohex-3-enyl, 3-fluorophenyl, tetrahydrofur-2-yl, pyrrolidin-l-yl, 4-methyltetrahydropyran-4-yl or thien-2-yl,

R<1>betegner hydrogen eller fluor, og R<1> denotes hydrogen or fluorine, and

R<2>betegner metyl-isoksazolyl, metyl-pyrazolyl, metyl-imidazoly1, benzimidazolyl eller metyl-triazolyl, forutsatt at når Z betegner 1-metylsyklobutyl, R<1>er hydrogen og R<2>betegner l-metyl-lH-l,2,4-triazol-3-yl eller 2-metyl-2H-1,2,4-triazol-3-yl, er fluoratomet ikke ved 2-stillingen av fenylringen. R<2>represents methyl-isoxazolyl, methyl-pyrazolyl, methyl-imidazolyl1, benzimidazolyl or methyl-triazolyl, provided that when Z represents 1-methylcyclobutyl, R<1>is hydrogen and R<2>represents l-methyl-lH- 1,2,4-triazol-3-yl or 2-methyl-2H-1,2,4-triazol-3-yl, the fluorine atom is not at the 2-position of the phenyl ring.

Visse forbindelser ifølge foreliggende oppfinnelse er omfattet innen den generiske ramme av internasjonal patent-søknad PCT/GB97/01946, publisert 5. februar 1998 som WO 98/04559. Det er imidlertid ingen spesifikk beskrivelse deri av forbindelser svarende til de av formel I som definert ovenfor. Certain compounds according to the present invention are covered within the generic framework of international patent application PCT/GB97/01946, published on February 5, 1998 as WO 98/04559. However, there is no specific description therein of compounds corresponding to those of formula I as defined above.

Foreliggende oppfinnelse tilveiebringer også en forbindelse av formel 1 som vist ovenfor, eller et farmasøytisk akseptabelt salt derav, hvori The present invention also provides a compound of formula 1 as shown above, or a pharmaceutically acceptable salt thereof, wherein

Z betegner trifluormetyl, 2-metylpropyl, 2,2-dimetyl-propyl, 3-metylbutyl, 1-fluorbut-3-enyl, syklobutyl, 1-metylsyklobutyl, 1-fluorsyklobutyl, 3-fluorsyklobutyl, 3-hydroksysyklobutyl, 3-benzyloksysyklobutyl, 1-metylsykloheksyl, syklopentylmetyl, pyrrolidin-l-yl Z denotes trifluoromethyl, 2-methylpropyl, 2,2-dimethyl-propyl, 3-methylbutyl, 1-fluorobut-3-enyl, cyclobutyl, 1-methylcyclobutyl, 1-fluorocyclobutyl, 3-fluorocyclobutyl, 3-hydroxycyclobutyl, 3-benzyloxycyclobutyl, 1-methylcyclohexyl, cyclopentylmethyl, pyrrolidin-1-yl

eller tien-2-yl, og or thien-2-yl, and

R<1>ogR<2>er som definert ovenfor, R<1>and R<2> are as defined above,

forutsatt at når Z betegner 1-metylsyklobutyl, R<1>er hydrogen og R<2>betegner l-metyl-lH-l,2,4-triazol-3-yl eller 2-metyl-2H-1,2,4-triazol-3-yl, er fluoratomet ikke ved 2-stillingen av fenylringen. provided that when Z represents 1-methylcyclobutyl, R<1>is hydrogen and R<2>represents 1-methyl-1H-1,2,4-triazol-3-yl or 2-methyl-2H-1,2,4 -triazol-3-yl, the fluorine atom is not at the 2-position of the phenyl ring.

Foreliggende oppfinnelse tilveiebringer enn videre en forbindelse av formel I som vist ovenfor eller et farmasøytisk akseptabelt salt derav, hvori: Z betegner syklobutyl, 1-metylsyklobutyl, 1-fluorsyklo butyl, 1-metylsykloheksyl, pyrrolidin-l-yl eller The present invention further provides a compound of formula I as shown above or a pharmaceutically acceptable salt thereof, wherein: Z denotes cyclobutyl, 1-methylcyclobutyl, 1-fluorocyclo butyl, 1-methylcyclohexyl, pyrrolidin-1-yl or

tien-2-yl, og thien-2-yl, and

R<1>ogR<2>er som definert ovenfor, R<1>and R<2> are as defined above,

forutsatt at når Z betegner 1-metylsyklobutyl, R<1>er hydrogen og R<2>betegner 1-metyl-lH-l,2,4-triazol-3-yl eller 2-metyl-2H-1,2,4-triazol-3-yl, er fluoratomet ikke ved 2-stillingen av fenylringen. provided that when Z represents 1-methylcyclobutyl, R<1> is hydrogen and R<2> represents 1-methyl-1H-1,2,4-triazol-3-yl or 2-methyl-2H-1,2,4 -triazol-3-yl, the fluorine atom is not at the 2-position of the phenyl ring.

For anvendelse innen medisin vil saltene av forbindelsene av formel I være farmasøytisk akseptable salter. Andre salter kan imidlertid være anvendbare ved fremstilling av forbindelser ifølge oppfinnelsen eller av deres farmasøytisk akseptable salter. Egnede farmasøytisk akseptable salter av forbindelsene ifølge oppfinnelsen, innbefatter syreaddisjons-salter som f.eks. kan dannes ved blanding av en løsning av forbindelsen ifølge oppfinnelsen med en løsning av en farma-søytisk akseptabel syre slik som saltsyre, svovelsyre, metan-sulfonsyre, fumarsyre, maleinsyre, ravsyre, eddiksyre, benzo-syre, oksalsyre, sitronsyre, vinsyre, karbonsyre eller fosfor-syre. For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds according to the invention include acid addition salts such as e.g. can be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

I forbindelsene av formel I ovenfor betegner gruppen Z hensiktsmessig syklobutyl. In the compounds of formula I above, the group Z suitably denotes cyclobutyl.

Substituenten R<2>betegner hensiktsmessig en ring av struktur (a), (b), (c), (d), (e), (f) eller (g): The substituent R<2> conveniently denotes a ring of structure (a), (b), (c), (d), (e), (f) or (g):

hvor stjernen<*>angir bindingspunktet av ringen til resten av molekylet. where the asterisk<*>indicates the attachment point of the ring to the rest of the molecule.

En særlig gruppe R<2>er representert ved struktur (g) som vist ovenfor. A particular group R<2> is represented by structure (g) as shown above.

Hvor det er tillatelig utviser forbindelsene av formel I som definert ovenfor, et fluoratom ved 2-stillingen av feny1ringen. Where permissible, the compounds of formula I as defined above exhibit a fluorine atom at the 2-position of the phenyl ring.

En spesiell underklasse av forbindelser ifølge oppfinnelsen er representert ved forbindelsene av formel IIA og farmasøytisk akseptable salter derav: A special subclass of compounds according to the invention is represented by the compounds of formula IIA and pharmaceutically acceptable salts thereof:

hvori in which

R<1>er som ovenfor definert, og R<1> is as defined above, and

R<3>betegner hydrogen eller fluor. R<3> denotes hydrogen or fluorine.

Hensiktsmessig betegner R<3>hydrogen. Conveniently, R<3> denotes hydrogen.

En spesiell undergruppe av forbindelsene av formel I IA ovenfor, er representert ved forbindelsene av formel UB og farmasøytisk akseptable salter derav: A special subgroup of the compounds of formula I IA above is represented by the compounds of formula UB and pharmaceutically acceptable salts thereof:

hvoriR<1>ogR<3>er som ovenfor definert. wherein R<1> and R<3> are as defined above.

Spesifikke forbindelser innen rammen for foreliggende oppfinnelse, innbefatter: 7-syklobutyl-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3 -ylmetoksy) -1,2,4-triazolo [ 4,3-b] pyr idazin, Specific compounds within the scope of the present invention include: 7-cyclobutyl-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4- triazolo[4,3-b]pyridazine,

7-syklobutyl-3-(2-fluorfenyl)-6-(1-metyl-1H-1,2,4-triazol-3-ylmetoksy )-l, 2,4-triazolo[4,3-b]pyridazin, 7-cyclobutyl-3-(2-fluorophenyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1, 2,4-triazolo[4,3-b]pyridazine,

7-syklobutyl-3-(3-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy )-l, 2,4-triazolo[4,3-b]pyridazin, 7-cyclobutyl-3-(3-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1, 2,4-triazolo[4,3-b]pyridazine,

7-syklobutyl-3-(4-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy) -1,2,4-triazolo [4,3-b] pyridazin, 7-cyclobutyl-3-(4-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine,

7-syklobutyl-3-{2,4-difluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-cyclobutyl-3-{2,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b] pyridazine,

7-syklobutyl-3-(3,5-difluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-cyclobutyl-3-(3,5-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b] pyridazine,

3-(2,4-difluorfenyl)-7-(1-metylsyklobutyl)-6-(2-metyl-2H-l, 2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b] - pyridazin, 3-(2,4-difluorophenyl)-7-(1-methylcyclobutyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4, 3-b] - pyridazine,

7-syklobutyl-3-(3,4-difluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-cyclobutyl-3-(3,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b] pyridazine,

7-syklobutyl-3-(2,3-difluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-cyclobutyl-3-(2,3-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b] pyridazine,

7-syklobutyl-3-(2,6-di fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-cyclobutyl-3-(2,6-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b ]pyridazine,

7-syklobutyl-3-(2,5-difluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-cyclobutyl-3-(2,5-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b] pyridazine,

3-(2,4-difluorfenyl)-7-(1-metylsykloheksyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b] - pyridazin, 3-(2,4-difluorophenyl)-7-(1-methylcyclohexyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4, 3-b] - pyridazine,

3-(2,4-difluorfenyl)-7-(1-metylsykloheksyl)-6-(1-metyl-lH-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]-pyridazin, 3-(2,4-difluorophenyl)-7-(1-methylcyclohexyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4, 3-b]-pyridazine,

7-syklobutyl-3-(2-fluorfenyl)-6- (1-metyl-lH-pyrazol-3- ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-cyclobutyl-3-(2-fluorophenyl)-6-(1-methyl-1H-pyrazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine,

7-syklobutyl-3-(2-fluorfenyl)-6-{5-metylisoksazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridaz in, 7-cyclobutyl-3-(2-fluorophenyl)-6-{5-methylisoxazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine,

7-syklobutyl-3-(2-fluorfenyl)-6- (1-metyl-lH-imidazol-2- ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-cyclobutyl-3-(2-fluorophenyl)-6-(1-methyl-1H-imidazol-2-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine,

7-syklobutyl-3-(2-fluorfenyl)-6 - {4-metyl-4H-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-cyclobutyl-3-(2-fluorophenyl)-6-{4-methyl-4H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine,

3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-yl-metoksy) -7-(tien-2-yl)-l,2,4-triazolo[4,3-b]pyridazin, 3-(2-Fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-yl-methoxy)-7-(thien-2-yl)-1,2,4-triazolo[ 4,3-b]pyridazine,

3-(2,4-difluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-7-(tien-2-yl)-l,2,4-triazolo[4,3-b]pyridazin, 3-(2,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-(thien-2-yl)-1,2,4-triazolo[ 4,3-b]pyridazine,

6- (lH-benzimidazol-2-ylmetoksy)-7-syklobutyl-3-(2,4-difluorfenyl)-1,2,4-triazolo[4,3-b]pyridazin, 6-(1H-benzimidazol-2-ylmethoxy)-7-cyclobutyl-3-(2,4-difluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine,

3-(2,4-difluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-7-(pyrrolidin-l-yl)-l,2,4-triazolo[4,3-b]pyridazin, 3-(2,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-(pyrrolidin-1-yl)-1,2,4-triazolo[ 4,3-b]pyridazine,

3-(2,4-difluorfenyl)-6-(1-metyl-lH-l,2,4-triazol-3-ylmetoksy)-7-(pyrrolidin-l-yl)-1,2,4-triazolo[4,3-b]pyridazin, 3-(2,4-difluorophenyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-(pyrrolidin-1-yl)-1,2,4-triazolo[ 4,3-b]pyridazine,

3-(2-fluorfenyl)-6-(1-metyl-lH-l,2,4-triazol-3-yl-metoksy)-7-(pyrrolidin-l-yl)-l,2,4-triazolo[4,3-b]pyridazin, 3-(2-fluorophenyl)-6-(1-methyl-1H-1,2,4-triazol-3-yl-methoxy)-7-(pyrrolidin-1-yl)-1,2,4-triazolo[ 4,3-b]pyridazine,

7- syklobutyl-3-(2-fluorfenyl)-6-(1-metyl-lH-imidazol-4- ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-cyclobutyl-3-(2-fluorophenyl)-6-(1-methyl-1H-imidazol-4-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine,

7-(l-fluorsyklobutyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-(1-fluorocyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3- b]pyridazine,

7-syklobutyl-3-(2-fluorfenyl)-6-(2-metyl-2H-pyrazol-3- ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-cyclobutyl-3-(2-fluorophenyl)-6-(2-methyl-2H-pyrazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine,

7-(2,2-dimetylpropyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-(2,2-dimethylpropyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4, 3-b]pyridazine,

3-(2-fluorfenyl)-7-(2-metylpropyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 3-(2-fluorophenyl)-7-(2-methylpropyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3- b]pyridazine,

3-{2-fluorfenyl)-7-(3-metylbutyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 3-{2-fluorophenyl)-7-(3-methylbutyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3- b]pyridazine,

7-syklopentylmetyl-3-(2-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-cyclopentylmethyl-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine,

7-(3-benzyloksysyklobutyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-(3-Benzyloxycyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3- b]pyridazine,

3-(2-fluorfenyl)-7-(3-hydroksysyklobutyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 3-(2-fluorophenyl)-7-(3-hydroxycyclobutyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3- b]pyridazine,

7-(1-fluorbut-3-eny1)-3-(2-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-(1-fluorobut-3-enyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[ 4,3-b]pyridazine,

7-(3-fluorsyklobutyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-(3-fluorocyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3- b]pyridazine,

3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-yl-metoksy)-7-trifluormetyl-1,2,4-triazolo[4,3-b]pyridazin, 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-yl-methoxy)-7-trifluoromethyl-1,2,4-triazolo[4,3-b] pyridazine,

3-(2-fluorfenyl)-7-(4-metyltetrahydropyran-4-yl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]-pyridazin, 3-(2-fluorophenyl)-7-(4-methyltetrahydropyran-4-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[ 4,3-b]-pyridazine,

3-(2-fluorfenyl)-7-(4-metyltetrahydropyran-4-yl)-6-(1-metyl-lH-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]-pyridazin, 3-(2-fluorophenyl)-7-(4-methyltetrahydropyran-4-yl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[ 4,3-b]-pyridazine,

7-(4,4-difluor-1-metylsykloheksyl)-3-(2-fluorfenyl)-6- (2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo-[4,3-b]pyridazin, 7-(4,4-difluoro-1-methylcyclohexyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4- triazolo-[4,3-b]pyridazine,

7-(4-fluor-1-metylsykloheks-3-enyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo-[4,3-b]pyridazin, 7-(4-fluoro-1-methylcyclohex-3-enyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2, 4-triazolo-[4,3-b]pyridazine,

7-(4,4-difluor-l-metylsykloheksyl)-3-(2-fluorfenyl)-6-{ 1-metyl-lH-l,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo-[4,3-b]pyridazin, 7-(4,4-difluoro-1-methylcyclohexyl)-3-(2-fluorophenyl)-6-{1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,4- triazolo-[4,3-b]pyridazine,

3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-yl-metoksy)-7-(3-oksosyklobutyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-yl-methoxy)-7-(3-oxocyclobutyl)-1,2,4-triazolo[4, 3-b]pyridazine,

7-(3,3-difluorsyklobutyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]-pyridazin. 7-(3,3-difluorocyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4, 3-b]-pyridazine.

3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-yl-metoksy)-7-(tetrahydrofur-2-yl)-l,2,4-triazolo[4,3-b]-pyridazin, 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-yl-methoxy)-7-(tetrahydrofur-2-yl)-1,2,4-triazolo[ 4,3-b]-pyridazine,

7-(3-fluorfenyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-(3-fluorophenyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3- b]pyridazine,

og farmasøytisk akseptable salter derav. and pharmaceutically acceptable salts thereof.

Også tilveiebragt ved foreliggende oppfinnelse er en metode for behandling og/eller forhindring av angst, som omfatter administrering til en pasient med behov for slik behandling, av en effektiv mengde av en forbindelse av formel I som definert ovenfor eller et farmasøytisk akseptabelt salt derav. Also provided by the present invention is a method for treating and/or preventing anxiety, which comprises administering to a patient in need of such treatment, an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof.

Ytterligere tilveiebragt ved foreliggende oppfinnelse er en metode for behandling og/eller forhindring av konvulsjoner (f.eks. en pasient som lider av epilepsi eller en be-slektet sykdom) som omfatter administrering til en pasient med behov for slik behandling, av en effektiv mengde av en forbindelse av formel I som definert ovenfor, eller et farmasøy-tisk akseptabelt salt derav. Further provided by the present invention is a method for the treatment and/or prevention of convulsions (e.g. a patient suffering from epilepsy or a related disease) which comprises administering to a patient in need of such treatment, an effective amount of a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof.

Bindingsaffiniteten ( Kt) av forbindelsene ifølge foreliggende oppfinnelse for ot3-subenheten av den humane GABAA-reseptor, måles hensiktsmessig ved den utprøvning som er beskrevet nedenfor. <x3-subenhet sbindingsaf f ini teten ( Kt) av forbindelsene ifølge oppfinnelsen er ideelt 10 nM eller mindre, fortrinnsvis 2 nM eller mindre og mer fordelaktig 1 nM eller mindre. The binding affinity (Kt) of the compounds according to the present invention for the ot3 subunit of the human GABAA receptor is appropriately measured by the test described below. The <x3-subunit binding affinity (Kt) of the compounds of the invention is ideally 10 nM or less, preferably 2 nM or less and more advantageously 1 nM or less.

Forbindelsene ifølge foreliggende oppfinnelse vil ideelt utøve minst en 40 %, fortrinnsvis minst en 50 %, og mer fordelaktig minst en 60 % potensiering av GABA EC20-responsen i stabilt transfiserte, rekombinante cellelinjer som uttrykker a3-subenheten av den humane GABAA-reseptor. Enn videre vil forbindelsene ifølge oppfinnelsen ideelt utvise maksimalt 30 %, fortrinnsvis maksimalt 20 %, og mer fordelaktig maksimalt 10 % potensiering av GABA EC20-responsen i stabilt transfiserte, rekombinante cellelinjer som uttrykker al-subenheten av den humane GABAA-reseptor. The compounds of the present invention will ideally exert at least a 40%, preferably at least a 50%, and more advantageously at least a 60% potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the α3 subunit of the human GABAA receptor. Furthermore, the compounds of the invention will ideally exhibit a maximum of 30%, preferably a maximum of 20%, and more advantageously a maximum of 10% potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the α1 subunit of the human GABAA receptor.

Potensieringen av GABA EC20-responsen i stabilt transfiserte cellelinjer som uttrykker a3- og al-subenheter av den humane GABAA-reseptor, kan hensiktsmessige måles ved prose dyrer analoge med den protokoll som er beskrevet 1 Wafford et al., Mol. Pharmacol., 1996, 50, 670-678. Prosedyren vil hensiktsmessig bli utført under anvendelse av kulturer av stabilt transfiserte, eukaryotiske celler, typisk av stabilt transfiserte muse-Ltk-fibroblastceller. The potentiation of the GABA EC20 response in stably transfected cell lines expressing α3 and α1 subunits of the human GABAA receptor can conveniently be measured by procedures analogous to the protocol described 1 Wafford et al., Mol. Pharmacol., 1996, 50, 670-678. The procedure will conveniently be carried out using cultures of stably transfected eukaryotic cells, typically of stably transfected mouse Ltk fibroblast cells.

Forbindelsene ifølge foreliggende oppfinnelse utviser anxiolytisk aktivitet som kan vises ved en positiv respons i den forøkte forvirrings- og betingede undertrykkelse av drikke-test (jf. Dawson et al., Psychopharmacology, 1995, 121, 109-117). Enn videre er forbindelsene ifølge oppfinnelsen hovedsakelig ikke-sedaterende, som kan bekreftes ved et egnet resultat erholdt fra responssensibilitetstesten (cf. Bayley et al., J. Psychopharmacol, 1996, 10, 206-213). The compounds according to the present invention exhibit anxiolytic activity which can be shown by a positive response in the increased confusion and conditioned suppression of drinking test (cf. Dawson et al., Psychopharmacology, 1995, 121, 109-117). Furthermore, the compounds according to the invention are mainly non-sedating, which can be confirmed by a suitable result obtained from the response sensitivity test (cf. Bayley et al., J. Psychopharmacol, 1996, 10, 206-213).

Forbindelsene ifølge oppfinnelsen kan også utøve antikonvulsiv aktivitet. Dette kan vises ved evnen til å blok-kere pentylentetrazolfremkalte anfall i rotte og mus, ved å følge en protokollanalog med den som er beskrevet av Bristow et al. i J. Pharmacol. Exp. Ther., 1996, 279, 492-501. The compounds according to the invention can also exert anticonvulsant activity. This can be demonstrated by the ability to block pentylenetetrazole-induced seizures in rats and mice, following a protocol analogous to that described by Bristow et al. in J. Pharmacol. Exp. Ther., 1996, 279, 492-501.

For å utøve deres adferdseffekter vil forbindelsene ifølge oppfinnelsen ideelt være hjerne-penetrerende, dvs. at disse forbindelser vil være i stand til å krysse den såkalte "blod-hjerne-barriere". Fortrinnsvis vil forbindelsene ifølge oppfinnelsen være i stand til å utøve deres gunstige terapeut-iske virkning etter administrering ved oral rute. In order to exert their behavioral effects, the compounds according to the invention will ideally be brain-penetrating, i.e. these compounds will be able to cross the so-called "blood-brain barrier". Preferably, the compounds according to the invention will be able to exert their beneficial therapeutic effect after administration by the oral route.

Oppfinnelsen tilveiebringer også farmasøytiske preparater omfattende én eller flere forbindelser ifølge oppfinnelsen i assosiasjon med en farmasøytisk akseptabel bærer. Fortrinnsvis er disse preparater i enhetsdoseringsform slik som tabletter, pillere, kapsler, pulvere, granuler, sterile, par-enterale løsninger eller suspensjoner, utmålte aerosol- eller væskespray, dråper, ampuller, autoinjeksjonsanordninger eller stikkpiller; for oral, parenteral, intranasal, sublingual eller rektal administrering, eller for administrering ved in-halering eller insufflasjon. For fremstilling av faste preparater slik som tabletter, blandes den prinsipale, aktive bestanddel med en farmasøytisk bærer, f.eks. konvensjonelle tabletter ingsbestanddeler slik som maisstivelse, laktose, suk-rose, sorbitol, talkum, stearinsyre, magnesiumstearat, di-kalsiumfosfat eller gummier, og andre farmasøytiske fortyn- ningsmidler, f.eks. vann, for å danne et fast preformuleringspreparat inneholdende en homogen blanding av en forbindelse ifølge oppfinnelsen, eller et farmasøytisk akseptabelt salt derav. Ved henvisning til disse preformuleringspreparater som homogene, menes det at den aktive bestanddel er dispergert igjen i preparatet, slik at preparatet lett kan oppdeles i like effektive enhetsdoseringsformer, slik som tabletter, pillere og kapsler. Dette faste preformuleringspreparat opp-telles deretter i enhetsdoseringsformer av den ovenfor beskrevne type, inneholdende fra 0,1 til ca. 500 mg aktiv bestanddel ifølge oppfinnelsen. Typiske enhetsdoseringsformer inneholder fra 1 til 100 mg, f.eks. 1, 2, 5, 10, 25, 50 eller 100 mg, av den aktive bestanddel. Tablettene eller pillene av det nye preparat kan belegges eller på annen måte sammensettes til å tilveiebringe en doseringsform som gir en forlenget virkning. Eksempelvis kan tabletten eller pillen omfatte en indre doserings- og en ytre doseringskomponent, hvor den sistnevnte er i form av en omhylling over den først nevnte. De to komponenter kan være separert med et enterisk lag som tjener til å motstå oppbrytning i magen og tillater at den indre komponent får passere intakt inn i duodenum eller til å bli forsinket i frigivelse. Et utall av materialer kan anvendes for slike enteriske lag eller belegg, og slike materialer innbefatter et utall av polymere syrer og blandinger av polymere syrer med slike materialer som skjellakk, cetylalkohol og cellulose-acetat. The invention also provides pharmaceutical preparations comprising one or more compounds according to the invention in association with a pharmaceutically acceptable carrier. Preferably, these are preparations in unit dosage form such as tablets, pills, capsules, powders, granules, sterile, parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjection devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For the production of solid preparations such as tablets, the principal, active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation preparation containing a homogeneous mixture of a compound according to the invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation preparations as homogeneous, it is meant that the active ingredient is dispersed again in the preparation, so that the preparation can be easily divided into equally effective unit dosage forms, such as tablets, pills and capsules. This solid preformulation preparation is then counted in unit dosage forms of the type described above, containing from 0.1 to approx. 500 mg active ingredient according to the invention. Typical unit dosage forms contain from 1 to 100 mg, e.g. 1, 2, 5, 10, 25, 50 or 100 mg of the active ingredient. The tablets or pills of the new preparation may be coated or otherwise compounded to provide a dosage form which provides a prolonged effect. For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, where the latter is in the form of an envelope over the first mentioned. The two components may be separated by an enteric layer which serves to resist breakdown in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release. A number of materials can be used for such enteric layers or coatings, and such materials include a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

De væskeformer i hvilke de nye preparater ifølge oppfinnelsen kan inkorporeres for administrering oralt eller ved injeksjon, innbefatter vandige løsninger, hensiktsmessige smakssatte siruper, vandige eller oljeaktige suspensjoner og smaksgitte emulsjoner med spiselige oljer, slik som bomulls-frøolje, sesamolje, kokosnøttolje eller peanøttolje, så vel som eliksirer og lignende farmasøytiske bærere. Egnede disper-gerings- eller suspenderingsmidler for vandige suspensjoner, innbefatter syntetiske og naturlige gummier, slik som tragant, akasie, alginat, dekstran, natriumkarboksymetylcellulose, metylcellulose, polyvinylpyrrolidon eller gelatin. The liquid forms in which the new preparations according to the invention can be incorporated for administration orally or by injection include aqueous solutions, suitable flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils, such as cottonseed oil, sesame oil, coconut oil or peanut oil, so as well as elixirs and similar pharmaceutical carriers. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums, such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

Ved behandling av angst er et egnet dosenivå ca. 0,01 til 250 mg/kg pr. dag, fortrinnsvis ca. 0,05 til 100 mg/kg pr. dag og spesielt ca. 0,05 til 5 mg/kg pr. dag. Forbindelsene kan administreres i et regime på 1 til 4 ganger pr. dag. When treating anxiety, a suitable dose level is approx. 0.01 to 250 mg/kg per day, preferably approx. 0.05 to 100 mg/kg per day and especially approx. 0.05 to 5 mg/kg per day. The compounds can be administered in a regimen of 1 to 4 times per day.

Forbindelsene av formel I som definert ovenfor, kan fremstilles i en fremgangsmåte som omfatter omsetning av en forbindelse av formel III med en forbindelse av formel IV: The compounds of formula I as defined above can be prepared in a process which comprises reacting a compound of formula III with a compound of formula IV:

hvori 2, R<1>og R<2>er som ovenfor definert og Ll betegner en egnet, forlatende gruppe. wherein 2, R<1> and R<2> are as defined above and L1 denotes a suitable leaving group.

Den forlatende gruppe L<1>er typisk et halogenatom, spesielt klor. The leaving group L<1> is typically a halogen atom, especially chlorine.

Reaksjonen mellom forbindelser III og IV utføres hensiktsmessig ved omrøring av reaktantene i et egnet løsnings-middel, typisk N,N-dimetylformamid eller tetrahydrofuran, i nærvær av en sterk base, slik som natriumhydrld, litium-bis-(trimetylsilyl)amid eller kalium-bis(trimetylsilyl)amid. The reaction between compounds III and IV is conveniently carried out by stirring the reactants in a suitable solvent, typically N,N-dimethylformamide or tetrahydrofuran, in the presence of a strong base, such as sodium hydride, lithium bis-(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide.

Mellomproduktene av formel III ovenfor kan fremstilles ved omsetning av en forbindelse av formel V med en hovedsakelig ekvimolar mengde av et hydrazinderivat av formel VI: The intermediates of formula III above can be prepared by reacting a compound of formula V with a substantially equimolar amount of a hydrazine derivative of formula VI:

hvori Z,R<1>ogL<1>er som ovenfor definert og L<2>betegner en egnet, forlatende gruppe; etterfulgt om nødvendig av separering av den resulterende blanding av isomerer på konvensjonell måte. wherein Z, R<1> and L<1> are as defined above and L<2> denotes a suitable leaving group; followed, if necessary, by separation of the resulting mixture of isomers by conventional means.

Den forlatende gruppe L<2>er typisk et halogenatom, spesielt klor. I mellomproduktene av formel V kan de forlatende grupper L<1>og L<2>være like eller forskjellige, men er hensiktsmessig de samme, fortrinnsvis begge klor. The leaving group L<2> is typically a halogen atom, especially chlorine. In the intermediates of formula V, the leaving groups L<1> and L<2> can be the same or different, but are suitably the same, preferably both chlorine.

Reaksjonen mellom forbindelsene V og VI utføres hensiktsmessig ved oppvarming av reaktantene i nærvær av en pro-tonkilde, slik som trietylamin-hydroklorid, typisk ved til-bakeløpstemperaturen i et inert løsningsmiddel, slik som xylen eller 1,4-dioksan. The reaction between compounds V and VI is conveniently carried out by heating the reactants in the presence of a proton source, such as triethylamine hydrochloride, typically at the reflux temperature in an inert solvent, such as xylene or 1,4-dioxane.

Alternativt kan mellomproduktene av formel III ovenfor fremstilles ved omsetning av et hydrazinderivat av formel VII med et aldehydderivat av formel VIII: Alternatively, the intermediates of formula III above can be prepared by reacting a hydrazine derivative of formula VII with an aldehyde derivative of formula VIII:

hvori Z, R<1>og Ll er som ovenfor definert; etterfulgt av syklisering av den derved erholdte, intermediære Schiffs base. wherein Z, R<1> and L1 are as defined above; followed by cyclization of the thus obtained intermediate Schiff's base.

Reaksjonene mellom forbindelser VII og VIII utføres hensiktsmessig under sure betingelser, f.eks. i nærvær av en mineralsyre, slik som saltsyre. Syklisering av det resulterende Schiffs base-mellomprodukt kan deretter hensiktsmessig utføres ved behandling med jem(III)-klorid i et egnet løsn-ingsmiddel, f.eks. et alkoholisk løsningsmiddel slik som etanol, ved en forhøyet temperatur, typisk ved en temperatur i området 60-70 °C. The reactions between compounds VII and VIII are conveniently carried out under acidic conditions, e.g. in the presence of a mineral acid, such as hydrochloric acid. Cyclization of the resulting Schiff's base intermediate can then conveniently be carried out by treatment with hem(III) chloride in a suitable solvent, e.g. an alcoholic solvent such as ethanol, at an elevated temperature, typically at a temperature in the range of 60-70 °C.

Mellomproduktene av formel VII ovenfor kan fremstilles ved omsetning av den egnede forbindelse av formel V som definert ovenfor, med hydrazinhydrat, typisk i 1,4-dioksan ved tilbakeløpstemperaturen for løsningsmidlet; etterfulgt om nødvendig av separering av den resulterende blanding av isomerer på konvensjonell måte. The intermediates of formula VII above can be prepared by reacting the appropriate compound of formula V as defined above, with hydrazine hydrate, typically in 1,4-dioxane at the reflux temperature of the solvent; followed, if necessary, by separation of the resulting mixture of isomers by conventional means.

Ved en alternativ metode kan mellomproduktene av formel III ovenfor fremstilles ved omsetning av hydrazin- derivatet av formel VII som definert ovenfor, med en forbindelse av formel IX: hvori R<1>er som ovenfor definert, og Q betegner en reaktiv kar-boksyl atgruppe; etterfulgt av syklisering av det derved erholdte hydrazidderivat av formel X: In an alternative method, the intermediates of formula III above can be prepared by reacting the hydrazine derivative of formula VII as defined above, with a compound of formula IX: wherein R<1> is as defined above, and Q denotes a reactive carboxyl group ; followed by cyclization of the thus obtained hydrazide derivative of formula X:

hvori Z, R<1>og L<1>er som ovenfor definert. in which Z, R<1>and L<1> are as defined above.

Egnede betydninger for den reaktive karboksylatgruppe Q innbefatter estere, f.eks. C1.4-alkylestere, syreanhydrider, f .eks. blandede anhydrider med C^-alkansyrer; syrehalogenid-er, f.eks. syreklorider; og acyliraidazoler. Hensiktsmessig betegner Q en syrekloridgruppe. Suitable meanings for the reactive carboxylate group Q include esters, e.g. C1.4-alkyl esters, acid anhydrides, e.g. mixed anhydrides with C 1 -alkanoic acids; acid halides, e.g. acid chlorides; and acyliraidazoles. Conveniently, Q denotes an acid chloride group.

Reaksjonen mellom forbindelser VII og IX utføres hensiktsmessig under basiske betingelser, f.eks. i nærvær av trietylamin, hensiktsmessig i et inert løsningsmiddel slik som dietyleter og typisk ved en temperatur innen området på 0 °C. Syklisering av den resulterende forbindelse av formel X kan deretter hensiktsmessig utføres ved behandling med 1,2-dibrom-1,1,2,2-tetrakloretan og trifenylfosfin, i nærvær av en base slik som trietylamin, hensiktsmessig i et inert løsningsmid-del, slik som acetonitril, og typisk ved en temperatur i området rundt 0 °C. The reaction between compounds VII and IX is conveniently carried out under basic conditions, e.g. in the presence of triethylamine, conveniently in an inert solvent such as diethyl ether and typically at a temperature in the range of 0°C. Cyclization of the resulting compound of formula X can then conveniently be carried out by treatment with 1,2-dibromo-1,1,2,2-tetrachloroethane and triphenylphosphine, in the presence of a base such as triethylamine, conveniently in an inert solvent, such as acetonitrile, and typically at a temperature in the region of 0 °C.

Reaksjonen mellom forbindelse V og hydrazinhydrat eller forbindelse VI vil, som ovenfor angitt, vanligvis gi opphav til en blanding av isomere produkter, avhengig av hvor-vidt hydrazinnitrogenatomet fortrenger den forlatende gruppe L<1>eller L<z>. I tillegg til det krevde produkt av formel III, vil således den isomere forbindelse, hvori gruppen Z er bundet: til 8-stillingen, vanligvis bli erholdt i en viss grad, og det samme for forbindelse VII. Av denne grunn vil det generelt være nødvendig å separere den resulterende blanding av isoraer-er ved konvensjonelle metoder slik som kromatografi. The reaction between compound V and hydrazine hydrate or compound VI will, as indicated above, usually give rise to a mixture of isomeric products, depending on the extent to which the hydrazine nitrogen atom displaces the leaving group L<1> or L<z>. Thus, in addition to the required product of formula III, the isomeric compound in which the group Z is attached: to the 8-position will usually be obtained to some extent, and the same for compound VII. For this reason, it will generally be necessary to separate the resulting mixture of isomers by conventional methods such as chromatography.

I en annen prosedyre kan forbindelsene av formel I som definert ovenfor, fremstilles ved en fremgangsmåte som omfatter omsetning av en forbindelse av formel XI [eller dens 1,2,4-triazolo[4,3-b]pyridazin-6-on-tautomer] med en forbindelse av formel XII: In another procedure, the compounds of formula I as defined above may be prepared by a process comprising reacting a compound of formula XI [or its 1,2,4-triazolo[4,3-b]pyridazin-6-one tautomer ] with a compound of formula XII:

hvori Z,R<1>og R<2>er som ovenfor definert, og L3 betegner en egnet forlatende gruppe. wherein Z, R<1> and R<2> are as defined above, and L3 denotes a suitable leaving group.

Den forlatende gruppe L<3>er hensiktsmessig et halo-gena tom, typisk klor eller brom. The leaving group L<3> is conveniently a halogen atom, typically chlorine or bromine.

Reaksjonen mellom forbindelser XI og XII utføres hensiktsmessig ved omrøring av reaktantene i et egnet løsnings-middel, typisk N,N-dimetylformamid, i nærvær av en sterk base, slik som natriumhydrid. The reaction between compounds XI and XII is conveniently carried out by stirring the reactants in a suitable solvent, typically N,N-dimethylformamide, in the presence of a strong base, such as sodium hydride.

Mellomproduktene av formel XI ovenfor kan hensiktsmessig fremstilles ved omsetning av en forbindelse av formel III som definert ovenfor, med et alkalimetallhydroksid, f.eks. natriumhydroksid. Reaksjonen utføres hensiktsmessig i et inert løsningsmiddel, slik som vandig 1,4-dioksan, ideelt ved løs-ningsmidlets tilbakeløpstemperatur. The intermediates of formula XI above can conveniently be prepared by reacting a compound of formula III as defined above, with an alkali metal hydroxide, e.g. sodium hydroxide. The reaction is conveniently carried out in an inert solvent, such as aqueous 1,4-dioxane, ideally at the reflux temperature of the solvent.

I en ytterligere prosedyre kan forbindelsene av formel I som definert ovenfor, fremstilles ved en fremgangsmåte som omfatter omsetning av en forbindelse av formel Z-C02H med en forbindelse av formel XIII: In a further procedure, the compounds of formula I as defined above can be prepared by a process comprising reacting a compound of formula Z-CO 2 H with a compound of formula XIII:

hvori Z, R<1>og R<2>er som ovenfor definert; i nærvær av sølv-nitrat og ammoniumpersulfat. wherein Z, R<1> and R<2> are as defined above; in the presence of silver nitrate and ammonium persulfate.

Reaksjonen utføres hensiktsmessig i et egnet løs-ningsmiddel, f.eks. vann eller vandig acetonitril, eventuelt under sure betingelser, f.eks. under anvendelse av svovelsyre, typisk ved en forhøyet temperatur. The reaction is suitably carried out in a suitable solvent, e.g. water or aqueous acetonitrile, optionally under acidic conditions, e.g. using sulfuric acid, typically at an elevated temperature.

Mellomproduktene av formel XIII svarer til forbindelsene av formel I som definert ovenfor, hvori Z er hydrogen, og disse kan derfor fremstilles ved metoder analoge med de som er beskrevet ovenfor for fremstilling av de tilsvarende forbindelser av formel I. The intermediates of formula XIII correspond to the compounds of formula I as defined above, in which Z is hydrogen, and these can therefore be prepared by methods analogous to those described above for the preparation of the corresponding compounds of formula I.

I en ytterligere prosedyre kan forbindelsene av formel I som definert ovenfor, fremstilles ved en fremgangsmåte som omfatter omsetning av en forbindelse av formel XIV med en forbindelse av formel XV: In a further procedure, the compounds of formula I as defined above can be prepared by a method comprising reacting a compound of formula XIV with a compound of formula XV:

hvori Z, R<1>og R<2>er som ovenfor definert, M betegner -B(OH)2eller -Sn(Alk)3, hvori Alk betegner en C^-alkylgruppe, typisk n-butyl, og L<*>betegner en egnet forlatende gruppe; i nærvær av en overgangsmetallkatalysator. in which Z, R<1> and R<2> are as defined above, M denotes -B(OH)2 or -Sn(Alk)3, in which Alk denotes a C 1 -alkyl group, typically n-butyl, and L<* >denotes a suitable leaving group; in the presence of a transition metal catalyst.

Den forlatende gruppe L<4>er hensiktsmessig et halo-gena tom , f.eks. brom. The leaving group L<4> is conveniently a halogen atom, e.g. bromine.

En egnet overgangsmetallkatalysator for anvendelse i reaksjonen mellom forbindelser XIV og XV, omfatter diklorbis- A suitable transition metal catalyst for use in the reaction between compounds XIV and XV includes dichlorobis-

(trifenylfosfin)palladium(II) eller tetrakis(trifenylfosfin)-palladium(O). (triphenylphosphine)palladium(II) or tetrakis(triphenylphosphine)palladium(O).

Reaksjonen mellom forbindelser XIV og XV utføres hensiktsmessig i et inert løsningsmiddel, slik som N,N-dimetyl-formamid, typisk ved en forhøyet temperatur. The reaction between compounds XIV and XV is conveniently carried out in an inert solvent, such as N,N-dimethylformamide, typically at an elevated temperature.

Mellomproduktene av formel XIV kan fremstilles ved omsetning av en forbindelse av formel IV som definert ovenfor, med en forbindelse av formel XVI: The intermediates of formula XIV can be prepared by reacting a compound of formula IV as defined above, with a compound of formula XVI:

hvori Z, L<1>og L<4>er som ovenfor definert; under betingelser analoge med de som er beskrevet ovenfor for reaksjonen mellom forbindelser III og IV. wherein Z, L<1> and L<4> are as defined above; under conditions analogous to those described above for the reaction between compounds III and IV.

I en ytterligere prosedyre kan forbindelsene av formel I, hvori Z betegner en 1-fluorsyklobutyl, fremstilles ved en fremgangsmåte som omfatter omsetning av en forbindelse av formel XVII: In a further procedure, the compounds of formula I, in which Z denotes a 1-fluorocyclobutyl, can be prepared by a method comprising the reaction of a compound of formula XVII:

hvori R<1>og R<2>er som ovenfor definert; med et fluoreringsmiddel. wherein R<1> and R<2> are as defined above; with a fluorinating agent.

På lignende måte kan forbindelser av formel I hvori Z betegner 3-fluorsyklobutyl eller 1-fluorbut-3-enyl eller en blanding derav, fremstilles ved en fremgangsmåte som omfatter omsetning av en forbindelse av formel XVIII: In a similar way, compounds of formula I in which Z denotes 3-fluorocyclobutyl or 1-fluorobut-3-enyl or a mixture thereof can be prepared by a method which comprises reacting a compound of formula XVIII:

hvoriR<1>og R2 er som ovenfor definert; med et fluoreringsmiddel. Hvor en blanding av produkter erholdes, kan de individuelle komponenter isoleres på konvensjonell måte, innbefattende kromatografi. wherein R<1>and R2 are as defined above; with a fluorinating agent. Where a mixture of products is obtained, the individual components can be isolated by conventional means, including chromatography.

På lignende måte kan forbindelser av formel I, hvori Z betegner 3,3-difluorsyklobutyl, fremstilles ved en fremgangsmåte som omfatter omsetning av den tilsvarende forbindelse, hvori Z betegner 3-oksosyklobutyl, med et fluoreringsmiddel. In a similar way, compounds of formula I, in which Z denotes 3,3-difluorocyclobutyl, can be prepared by a method comprising reacting the corresponding compound, in which Z denotes 3-oxocyclobutyl, with a fluorinating agent.

Et egnet fluoreringsmiddel for anvendelse i de ovenfor angitte reaksjoner, er dietylaminosvoveltrifluorid.(DAST), i hvilket tilfelle reaksjonen hensiktsmessig kan bevirkes ved omrøring av reaktantene i et inert løsningsmiddel, slik som diklormetan, typisk ved en temperatur i området rundt -78 °C. A suitable fluorinating agent for use in the above-mentioned reactions is diethylaminosulphur trifluoride (DAST), in which case the reaction can conveniently be effected by stirring the reactants in an inert solvent, such as dichloromethane, typically at a temperature in the region of -78 °C.

Mellomproduktene av formel XVII kan fremstilles ved omsetning av en forbindelse av formel IV som definert ovenfor, med en forbindelse av formel XIX: The intermediates of formula XVII can be prepared by reacting a compound of formula IV as defined above, with a compound of formula XIX:

hvori R<1>og L<1>er som ovenfor definert; under betingelser analoge med de som er beskrevet ovenfor for reaksjonen mellom forbindelser III og IV. wherein R<1> and L<1> are as defined above; under conditions analogous to those described above for the reaction between compounds III and IV.

Mellomproduktene av formel XIX kan i sin tur fremstilles ved omsetning av syklobutanon med en forbindelse av formel XX: The intermediates of formula XIX can in turn be prepared by reacting cyclobutanone with a compound of formula XX:

hvoriR<1>og L<1>er som ovenfor definert, og Alk betegner C^g-alkyl, typisk metyl. wherein R<1> and L<1> are as defined above, and Alk denotes C1-6-alkyl, typically methyl.

Reaksjonen utføres hensiktsmessig ved behandling av reagensene med en fluoridkilde, f.eks. en katalytisk mengde av tetrabutylammoniumdifluortrifenylstannat, hensiktsmessig i et inert løsningsmiddel slik som tetrahydrofuran. The reaction is conveniently carried out by treating the reagents with a fluoride source, e.g. a catalytic amount of tetrabutylammonium difluorotriphenylstannate, suitably in an inert solvent such as tetrahydrofuran.

Mellomproduktene av formel XX svarer til forbindelsene av formel III som definert ovenfor, hvori Z er -Si(Alk)3, og de kan derfor fremstilles ved metoder analoge med de som er beskrevet ovenfor for fremstilling av de tilsvarende forbindelser av formel III. The intermediates of formula XX correspond to the compounds of formula III as defined above, in which Z is -Si(Alk) 3 , and they can therefore be prepared by methods analogous to those described above for the preparation of the corresponding compounds of formula III.

Forbindelsene av formel XVIIIovenfor (svarende til forbindelser av formel I, hvori Z betegner 3-hydroksysyklobutyl) kan fremstilles ved hydrogenolyse av en forbindelse av formel XXI: The compounds of formula XVIII above (corresponding to compounds of formula I, in which Z denotes 3-hydroxycyclobutyl) can be prepared by hydrogenolysis of a compound of formula XXI:

hvoriR<1>og R<2>er som definert ovenfor. wherein R<1> and R<2> are as defined above.

Reaksjonen utføres hensiktsmessig ved overførings-hydrogenering, som omfatter å bringe forbindelse XXI i kontakt med en hydrogeneringskatalysator i nærvær av en hydrogendonor. En egnet hydrogeneringskatalysator er palladium på karbon, ideelt 10 % palladium på karbon. En egnet hydrogendonor er ammoniumformiat, i hvilket tilfelle reaksjonen fordelaktig ut-føres i maursyre. The reaction is conveniently carried out by transfer hydrogenation, which involves contacting compound XXI with a hydrogenation catalyst in the presence of a hydrogen donor. A suitable hydrogenation catalyst is palladium on carbon, ideally 10% palladium on carbon. A suitable hydrogen donor is ammonium formate, in which case the reaction is advantageously carried out in formic acid.

I en ytterligere prosedyre kan forbindelsene av formel I som definert ovenfor, fremstilles ved en fremgangsmåte som omfatter omsetning av en forbindelse av formel XXII med en forbindelse av formel XXIII: In a further procedure, the compounds of formula I as defined above can be prepared by a method comprising reacting a compound of formula XXII with a compound of formula XXIII:

hvori Z,R1 og R<2>er som ovenfor definert, L5 betegner en egnet forlatende gruppe og E betegner -B(OH)2eller residuet av et organosinkreagens; i nærvær av en overgangsmetallkatalysator. wherein Z, R1 and R<2> are as defined above, L5 denotes a suitable leaving group and E denotes -B(OH)2 or the residue of an organozinc reagent; in the presence of a transition metal catalyst.

Den forlatende gruppe L<5>er hensiktsmessig et halo-gena tom, f.eks. brom eller jod. The leaving group L<5> is conveniently a halogen atom, e.g. bromine or iodine.

Hvor E betegner -B(OH)2, er overgangsmetallkatalysatoren for anvendelse i reaksjonen mellom forbindelser XXII og XXIII, hensiktsmessig tetrakis(trifenylfosfin)palladium(O), og reaksjonen utføres hensiktsmessig ved en forhøyet temperatur i nærvær av kaliumfosfat og et løsningsmiddel, slik som N,N-di-mety1formamid. Where E represents -B(OH)2, the transition metal catalyst for use in the reaction between compounds XXII and XXIII is suitably tetrakis(triphenylphosphine)palladium(O), and the reaction is suitably carried out at an elevated temperature in the presence of potassium phosphate and a solvent, such as N,N-Dimethylformamide.

Hvor E betegner resten av et organosinkreagens, fremstilles hensiktsmessig mellomproduktet XXIII ved omsetning av et jodidderivat Z-I med sinkstøv, typisk i nærvær av 1,2-dibrometan og et løsningsmiddel slik som N,N-diraetylformamid. I dette tilfellet er overgangsmetallkatalysatoren for anvendelse i reaksjonen mellom forbindelser XXII og XXIII ideelt tris(di-benzylidenaceton)dipalladium(O) og reaksjonen utføres hensiktsmessig i nærvær av tri-2-furylfosfin og et løsningsmiddel slik som N,N-dimetylformamid. Where E denotes the residue of an organozinc reagent, the intermediate XXIII is suitably prepared by reacting an iodide derivative Z-I with zinc dust, typically in the presence of 1,2-dibromoethane and a solvent such as N,N-diethylformamide. In this case, the transition metal catalyst for use in the reaction between compounds XXII and XXIII is ideally tris(di-benzylideneacetone)dipalladium(O) and the reaction is conveniently carried out in the presence of tri-2-furylphosphine and a solvent such as N,N-dimethylformamide.

Forbindelsene av formel XXI ovenfor (svarende til forbindelser av formel I, hvori Z betegner 3-benzyloksysyklobutyl) kan fremstilles på lignende måte ved omsetning av en forbindelse av formel XXII, som definert ovenfor, med en forbindelse av formel XXIV: The compounds of formula XXI above (corresponding to compounds of formula I, in which Z denotes 3-benzyloxycyclobutyl) can be prepared in a similar manner by reacting a compound of formula XXII, as defined above, with a compound of formula XXIV:

hvori E er som ovenfor definert; i nærvær av en overgangsmetallkatalysator; under betingelser analoge med de som er beskrevet ovenfor for reaksjonen mellom forbindelser XXII og wherein E is as above defined; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds XXII and

XXIII. XXIII.

Mellomproduktene av formel XXII kan fremstilles ved omsetning av en forbindelse av formel IV, som definert ovenfor, med en forbindelse av formel XXV: The intermediates of formula XXII can be prepared by reacting a compound of formula IV, as defined above, with a compound of formula XXV:

hvori R<1>, L<1>og L5 er som ovenfor definert; under betingelser analoge med de som er beskrevet ovenfor for reaksjonen mellom forbindelser III og IV. wherein R<1>, L<1> and L5 are as defined above; under conditions analogous to those described above for the reaction between compounds III and IV.

Mellomproduktene av formel XXV kan hensiktsmessig fremstilles ved behandling av den egnede forløper av formel XX som definert ovenfor, med en fluoridkilde, f.eks. tetrabutyl-atnmoniumdif luortrif enylstannat eller tris(dimetylamino)svovel-(trimetyl)difluorid, i nærvær av et L<5->holdig reagens, f.eks. 1,2-dibromtetrafluoretan eller 1,2-dijodetan. The intermediates of formula XXV may conveniently be prepared by treating the appropriate precursor of formula XX as defined above, with a fluoride source, e.g. tetrabutylammonium difluortrifenyl stannate or tris(dimethylamino)sulfur-(trimethyl)difluoride, in the presence of an L<5>-containing reagent, e.g. 1,2-dibromotetrafluoroethane or 1,2-diiodoethane.

Forbindelsene av formel I som definert ovenfor, hvori Z betegner trifluormetyl, kan fremstilles ved en fremgangsmåte som omfatter omsetning av en forbindelse av formel XXII, som definert ovenfor, med jodtrifluormetan. The compounds of formula I as defined above, in which Z denotes trifluoromethyl, can be prepared by a process comprising reacting a compound of formula XXII, as defined above, with iodotrifluoromethane.

Reaksjonen utføres hensiktsmessig i nærvær av kopperpulver, typisk i et forseglet rør ved en forhøyet temperatur, f.eks. en temperatur i området rundt 80 °C. The reaction is conveniently carried out in the presence of copper powder, typically in a sealed tube at an elevated temperature, e.g. a temperature in the region of around 80 °C.

Mellomproduktene av formel IV ovenfor kan fremstilles ved de prosedyrer som er beskrevet i EP-A-0421210 eller ved metoder analoge dertil. The intermediates of formula IV above can be prepared by the procedures described in EP-A-0421210 or by methods analogous thereto.

Hvor det ikke er kommersielt tilgjengelig, kan ut-gangsmaterialene av formel V, VI, VIII, IX, XII, XV, XVI og XXIV fremstilles ved metoder analoge med de som er beskrevet i de medfølgende eksempler, eller ved standard metoder vel kjent innen faget. Where not commercially available, the starting materials of formula V, VI, VIII, IX, XII, XV, XVI and XXIV can be prepared by methods analogous to those described in the accompanying examples, or by standard methods well known in the art .

Under enhver av de ovenfor beskrevne syntesesekvens-er, kan det være nødvendig og/eller ønskelig å beskytte sensi-tive eller reaktive grupper på enhver av de angjeldende mole-kyler. Dette kan oppnås ved hjelp av konvensjonelle, beskyttende grupper, slik som de som er beskrevet i Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; og T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. De beskyttende grupper kan fjernes ved et hensiktsmessig, etterfølgende trinn under anvendelse av metoder velkjent innen faget. During any of the synthesis sequences described above, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the relevant molecules. This can be achieved using conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protective groups can be removed in an appropriate subsequent step using methods well known in the art.

De etterfølgende eksempler illustrerer fremstilling av forbindelser ifølge oppfinnelsen. The following examples illustrate the preparation of compounds according to the invention.

Forbindelsene ifølge oppfinnelsen inhiberer kraftig bindingen av [<3>H]-flumazenil til det benzodiazepinbindende sete av humane GABAA-reseptorer inneholdende a2- eller a3-subenheten, stabilt uttrykt i Ltk-celler. The compounds according to the invention strongly inhibit the binding of [<3>H]-flumazenil to the benzodiazepine-binding site of human GABAA receptors containing the α2 or α3 subunit, stably expressed in Ltk cells.

Reagenser Reagents

Fosfatbuffret saltvann (PBS) Phosphate buffered saline (PBS)

Prøvebuffer: 10 mM KH2P04, 100 mM KC1, pH 7,4 ved Sample buffer: 10 mM KH2PO4, 100 mM KC1, pH 7.4 at

romtemperatur. room temperature.

[<3>H]-flumazenil (18 nM for alp3y2-celler; 18 nM for a2p3y2-celler; 10 nM for ot3P3y2-celler) i prøve-buffer. [<3>H]-flumazenil (18 nM for alp3y2 cells; 18 nM for a2p3y2 cells; 10 nM for ot3P3y2 cells) in sample buffer.

Flunitrazepam 100 uM i brøvebuffer. Flunitrazepam 100 uM in buffer.

Celler resuspendert i prøvebuffer (1 trau til 10 ml). Cells resuspended in sample buffer (1 trough to 10 ml).

Høsting av celler Harvesting of cells

Supernatant fjernes fra cellene. PBS (ca. 20 ml) til-settes. Cellene skrapes og anbringes i et 50 ml sentrifugerør. Prosedyren gjentas med ytterligere 10 ml PBS for å sikre at mesteparten av cellene fjernes. Cellene pelleteres ved sentri-fugering i 20 min ved 3 000 opm i en "benchtop"-sentrifuge, og fryses deretter om ønsket. Pelletene resuspenderes i 10 ml buffer pr. trau (25 cm x 25 cm) av celler. Supernatant is removed from the cells. PBS (approx. 20 ml) is added. The cells are scraped and placed in a 50 ml centrifuge tube. The procedure is repeated with an additional 10 ml of PBS to ensure that most of the cells are removed. The cells are pelleted by centrifugation for 20 min at 3,000 rpm in a "benchtop" centrifuge, and then frozen if desired. The pellets are resuspended in 10 ml of buffer per trough (25 cm x 25 cm) of cells.

Utprøvning Trial

Kan utføres 1 dype 96-brønns plater eller i rør. Hvert rør inneholder: Can be carried out in 1 deep 96-well plates or in tubes. Each tube contains:

300 ul prøvebuffer. 300 µl sample buffer.

50 ul [<3>H]-flumazenil (slut tkonsent ras jon for otlp3y2: 1,8 nM; for a2P3y2: 1,8 nM; for a3P3y2: 1,0 nM). 50 µl [<3>H]-flumazenil (final concentration for otlp3y2: 1.8 nM; for a2P3y2: 1.8 nM; for a3P3y2: 1.0 nM).

50 ul av buffer eller løsnlngsmiddelbærer (f.eks. 50 ul of buffer or solvent carrier (e.g.

10 % DMSO) hvis forbindelsene er oppløst i 10 % DMS0 10% DMSO) if the compounds are dissolved in 10% DMS0

(totalt); testforbindelse eller flunitrazepam (for å bestemme ikke-spesifikk binding), 10 uM sluttkonsen-trasjon. (total); test compound or flunitrazepam (to determine non-specific binding), 10 µM final concentration.

100 ul av celler. 100 µl of cells.

Prøvene inkuberes ilt ved 40 °C, filtreres deretter under anvendelse av enten en Tomtee- eller Brandel-cellehøster på GF/B-filtere, etterfulgt av 3 x 3 ml vasking med iskald prøvebuffer. Filtrene tørkes og telles ved væskescintilla-sjonstelling. Forventede verdier for total binding er 3 000-4 000 dpm for totale tellinger, og mindre enn 200 dpm for ikke-spesifikk binding ved anvendelse av væskescintillasjons-telling, eller 1 500-2 000 dpm for totale tellinger og mindre enn 200 dpm for ikke-spesifikk binding hvis tellingen utføres med meltilex fast seintiUant. Bindingsparametere bestemmes ved ikke-lineære minste kvadraters regresjonsanalyse, fra hvilken inhiberingskonstanten Ktkan beregnes for hver testforbindelse. The samples are incubated in oxygen at 40°C, then filtered using either a Tomtee or Brandel cell harvester on GF/B filters, followed by 3 x 3 ml washes with ice-cold sample buffer. The filters are dried and counted by liquid scintillation counting. Expected values for total binding are 3,000-4,000 dpm for total counts, and less than 200 dpm for non-specific binding using liquid scintillation counting, or 1,500-2,000 dpm for total counts and less than 200 dpm for non -specific binding if the count is carried out with meltilex fixed seintiUant. Binding parameters are determined by non-linear least squares regression analysis, from which the inhibition constant Kt can be calculated for each test compound.

Forbindelsene ifølge de etterfølgende eksempler ble testet i den ovenfor beskrevne utprøvning, og alle ble funnet å utvise en Kt-verdi for fortrenging av [<3>H]-flumazenil fra a.2-og/eller a3-subenheten av den humane GABAR-reseptor på 100 nM eller mindre. The compounds of the following examples were tested in the assay described above and all were found to exhibit a Kt value for the displacement of [<3>H]-flumazenil from the α2 and/or α3 subunit of the human GABAR receptor of 100 nM or less.

Eksem4 pel 1 Eczema 4 pel 1

7- syklobutyl- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol- 3-ylmetoksy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 2- fluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol- 3-ylmethoxy)- 1, 2, 4- triazolo[ 4, 3-b] pyridazine

a) 3, 6- diklor- 4- syklobutylpyrldazln a) 3, 6-dichloro-4-cyclobutylpyrldazln

Konsentrert svovelsyre (53,6 ml, 1,0 mol) ble forsiktig tilsatt til en omrørt suspensjon av 3,6-diklorpyridazin (50,0 g, 0,34 mol) i 1,25 1 vann. Denne blanding ble deretter oppvarmet til 70 °C (indre temperatur) før tilsetning av syklobutankarboksylsyre (35,3 ml, 0,37 mol). En løsning av sølv-nitrat (11,4 g, 0,07 mol) i 20 ml vann ble deretter tilsatt i løpet av tilnærmet ett minutt. Dette forårsaket at reaksjonsblandingen ble melkeaktig i utseende. En løsning av ammoniumpersulfat (230 g, 1,0 mol) i 0,63 1 vann ble deretter tilsatt i løpet av 20-30 min. Den indre temperatur steg til ca. 85 °C. Under tilsetningen ble produktet dannet som et klebrig bunn-fall. Etter fullførelse av tilsetningen ble reaksjonsblandingen omrørt i ytterligere 5 min, fikk deretter avkjøles til romtemperatur. Blandingen ble deretter helt over i is og gjort basisk med konsentrert vandig ammoniakk og med tilsetning av mer is etter behov for å holde temperaturen under 10 °C. Den vandige fase ble ekstrahert 3 ganger med diklormetan. De kombinerte ekstrakter ble tørket (MgS04), ble filtrert og fordampet under dannelse av tittelforbindelsen (55,7 g, 82 %) som en olje.<*>H nmr (CDC13) indikerte forurensning med ca. 5 % av 4, 5-disyklobutylforbindelsen. Dette materialet ble imidlertid anvendt uten ytterligere rensing. Data for tittelforbindelsen:<*>H NMR (360 MHz, d6-DMS0) 5 1,79-1,90 (1 H, m), 2,00-2,09 (1 H, m), 2,18-2,30 (2 H, m), 2,33-2,40 (2 H, m), 3,63-3,72 (1 H, m), 7,95 (1 H, s); Concentrated sulfuric acid (53.6 mL, 1.0 mol) was carefully added to a stirred suspension of 3,6-dichloropyridazine (50.0 g, 0.34 mol) in 1.25 L of water. This mixture was then heated to 70 °C (internal temperature) before addition of cyclobutanecarboxylic acid (35.3 mL, 0.37 mol). A solution of silver nitrate (11.4 g, 0.07 mol) in 20 mL of water was then added over approximately one minute. This caused the reaction mixture to become milky in appearance. A solution of ammonium persulfate (230 g, 1.0 mol) in 0.63 L of water was then added over 20-30 min. The internal temperature rose to approx. 85 °C. During the addition, the product formed as a sticky bottom drop. After completion of the addition, the reaction mixture was stirred for an additional 5 min, then allowed to cool to room temperature. The mixture was then poured into ice and basified with concentrated aqueous ammonia and with the addition of more ice as needed to keep the temperature below 10°C. The aqueous phase was extracted 3 times with dichloromethane. The combined extracts were dried (MgSO 4 ), filtered and evaporated to give the title compound (55.7 g, 82%) as an oil.<*>H nmr (CDCl 3 ) indicated contamination with ca. 5% of the 4,5-dicyclobutyl compound. However, this material was used without further purification. Data for the title compound:<*>H NMR (360 MHz, d 6 -DMSO) δ 1.79-1.90 (1 H, m), 2.00-2.09 (1 H, m), 2.18- 2.30 (2H, m), 2.33-2.40 (2H, m), 3.63-3.72 (1H, m), 7.95 (1H, s);

MS (ES<+>) m/e 203 [MH]<+>, 205 [MH] + , 207 [MH]\ MS (ES<+>) w/e 203 [MH]<+>, 205 [MH] + , 207 [MH]\

b) 6- klor- 7- syklobutyl- 3-( 2- fluorfenyl)- l, 2, 4- triazolo- [ 4, 3- blpyridazin b) 6- chloro- 7- cyclobutyl- 3-( 2- fluorophenyl)- 1, 2, 4- triazolo- [ 4, 3- blpyridazine

En blanding av 3,6-diklor-4-syklobutylpyridazin erholdt ovenfor (3,0 g, 14,7 mmol), 2-fluorbenzhydrazid (3,0 g, 19,5 mmol) og trietylamin-hydroklorid (3,0 g, 21,8 mmol) i p-xylen (50 ml) ble omrørt og oppvarmet til tilbakeløpskoking under en strøm av nitrogen i 20 t. Etter avkjøling ble de flyktige bestanddeler fjernet i vakuum. Residuet ble fordelt mellom diklormetan og vann. Den vandige fase ble gjort basisk ved tilsetning av fast kaliumkarbonat. Noe mørkt uløselig materiale ble fjernet ved filtrering ved dette trinn. Den vandige fase ble ytterligere ekstrahert 2 ganger med diklormetan. De kombinerte ekstrakter ble tørket (MgS04), ble filtrert og fordampet. Residuet ble renset ved kromatografi på silikagel og ble eluert med 20 % -> 30 % etylacetat/diklormetan under dannelse av tittelforbindelsen (2,2 g, 49 %) som et lyst brunt, fast materiale. Data for tittelforbindelsen:<l>H NMR (250 MHz, CDC13) 5 1,85-2,08 (1 H, m)., 2,08-2,30 (3 H, m), 2,38-2,64 (2 H, m), 3,62-3,84 (1 H, m), 7,19-7,46 (2 H, m), 7,46-7,67 (1 H, m), 7,80-7,96 (1 H, m), 7,99 A mixture of 3,6-dichloro-4-cyclobutylpyridazine obtained above (3.0 g, 14.7 mmol), 2-fluorobenzhydrazide (3.0 g, 19.5 mmol) and triethylamine hydrochloride (3.0 g, 21.8 mmol) in p-xylene (50 mL) was stirred and heated to reflux under a stream of nitrogen for 20 h. After cooling, the volatiles were removed in vacuo. The residue was partitioned between dichloromethane and water. The aqueous phase was made basic by the addition of solid potassium carbonate. Some dark insoluble material was removed by filtration at this step. The aqueous phase was further extracted twice with dichloromethane. The combined extracts were dried (MgSO 4 ), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 20% -> 30% ethyl acetate/dichloromethane to give the title compound (2.2 g, 49%) as a light brown solid. Data for the title compound: <1>H NMR (250 MHz, CDCl 3 ) δ 1.85-2.08 (1 H, m), 2.08-2.30 (3 H, m), 2.38-2 .64 (2 H, m), 3.62-3.84 (1 H, m), 7.19-7.46 (2 H, m), 7.46-7.67 (1 H, m) , 7.80-7.96 (1 H, m), 7.99

(1 H, s); (1H, s);

MS (ES<*>) m/e 303 [MH]\ 305 [MH] + . MS (ES<*>) m/e 303 [MH]\ 305 [MH] + .

c) 7- syklobutyl- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4-triazol- 3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin c) 7-cyclobutyl-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b] pyridazine

Til en løsning av (2-metyl-2H-l,2,4-triazol-3-yl)-metanol (0,123 g, 1,09 mmol) (fremstilt under anvendelse av betingelsene beskrevet i EP-A-421210) i 15 ml DMF ble det tilsatt natriumhydrid (0,044 g av en 60 % dispersjon i olje, To a solution of (2-methyl-2H-1,2,4-triazol-3-yl)-methanol (0.123 g, 1.09 mmol) (prepared using the conditions described in EP-A-421210) in 15 ml of DMF was added sodium hydride (0.044 g of a 60% dispersion in oil,

1,1 mol ekvivalenter) og reaksjonsblandingen ble omrørt ved romtemperatur i 30 min. Etter den periode ble det foregående produkt (0,3 g, 0,99 mmol) tilsatt som en løsning i 15 ml DMF og reaksjonsblandingen ble omrørt ved romtemperatur i 2 t. Reaksjonsblandingen ble fortynnet med 100 ml vann og den vandige fase ble ekstrahert med 4 x 100 ml diklormetan. De kombinerte ekstrakter ble tørket (Na2S04), ble filtrert og fordampet. Residuet ble renset ved kromatografi på silikagel under anvendelse av 2 % MeOH i diklormetan som elueringsmiddel, under dannelse av detønskede produkt (0,294 g, 78 %). 1.1 mol equivalents) and the reaction mixture was stirred at room temperature for 30 min. After that period, the preceding product (0.3 g, 0.99 mmol) was added as a solution in 15 mL DMF and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with 100 mL water and the aqueous phase was extracted with 4 x 100 ml dichloromethane. The combined extracts were dried (Na 2 SO 4 ), filtered and evaporated. The residue was purified by chromatography on silica gel using 2% MeOH in dichloromethane as eluent to give the desired product (0.294 g, 78%).

1H-NMR (250 MHz, CDC13) 8 1,82-2,00 (1 H, m), 2,00-2,26 (3 H, m), 2,26-2,48 (2 H, m), 3,53-3,70 (1 H, m), 3,84 1H-NMR (250 MHz, CDCl 3 ) 8 1.82-2.00 (1 H, m), 2.00-2.26 (3 H, m), 2.26-2.48 (2 H, m ), 3.53-3.70 (1 H, m), 3.84

(3 H, s), 5,47 (2 H, s), 7,22-7,42 (2 H, m), 7,50-7,64 (1 H, m), 7,76-7,96 (3 H, rn); (3 H, s), 5.47 (2 H, s), 7.22-7.42 (2 H, m), 7.50-7.64 (1 H, m), 7.76-7 .96 (3 H, rn);

MS (ES<*>) m/e 380 [MH]\ MS (ES<*>) m/e 380 [MH]\

Anal. funnet C 60,21, H 4,77, N 25,66 %. Anal. found C 60.21, H 4.77, N 25.66%.

Cl9H18FN70 kreves C 60,15, H 4,78, N 25,84 %. Cl9H18FN70 required C 60.15, H 4.78, N 25.84%.

Eksempel 2 Example 2

7- syklobutyl- 3-( 2- fluorfenyl)- 6-( 1- metyl- lH- l, 2 , 4- triazol- 3-ylmetoksy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 2- fluorophenyl)- 6-( 1- methyl- 1H- 1, 2 , 4- triazol- 3-ylmethoxy)- 1, 2, 4- triazolo[ 4, 3-b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyrene beskrevet i eksempel 1, trinn a), b) og c), med (1-metyl-lH-l,2,4-triazol-3-yl)metanol (fremstilt under anvendelse av betingelsene beskrevet i EP-A-421210) anvendt i stedet for (2-metyl-2H-l,2,4-triazol-3-yl)metanol i trinn c). Data for tittelforbindelsen:<X>H-NMR (360 MHz, d6-DMS0) 8 1,74-1,87 (1 H, m), 1,94-2,08 (1 H, m), 2,14-2,34 (4 H, m), 3,50-3,64 (1 H, m), 3,87 (3 H, s), 5,30 (2 H, s), 7,41-7,51 (2 H, m), 7,62-7,70 (1 H, m), 7,96-8,03 (1 H, m), 8,14 (1 H, s), 8,50 (1 H, s); This compound was prepared using the procedures described in Example 1, steps a), b) and c), with (1-methyl-1H-1,2,4-triazol-3-yl)methanol (prepared using the conditions described in EP-A-421210) used instead of (2-methyl-2H-1,2,4-triazol-3-yl)methanol in step c). Data for the title compound:<X>H-NMR (360 MHz, d6-DMS0) 8 1.74-1.87 (1 H, m), 1.94-2.08 (1 H, m), 2.14 -2.34 (4 H, m), 3.50-3.64 (1 H, m), 3.87 (3 H, s), 5.30 (2 H, s), 7.41-7 .51 (2 H, m), 7.62-7.70 (1 H, m), 7.96-8.03 (1 H, m), 8.14 (1 H, s), 8.50 (1H, s);

MS (ES<+>) m/e 380 [MH]<+>. MS (ES<+>) m/e 380 [MH]<+>.

Eksempel 3 Example 3

7- syklobutyl- 3-( 3- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol- 3-ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyrldazln 7- cyclobutyl- 3-( 3- fluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol- 3-ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyrldazln

Denne forbindelse ble fremstilt under anvendelse av prosedyrene beskrevet i eksempel 1, trinn a), b) og c) under anvendelse av 3-fluorbenzhydrazid i stedet for 2-fluorbenzhydrazid i trinn b). Data for tittelforbindelsen:<*>H-NMR (250 MHz, d6-DMS0) 6 1,74-1,90 (1 H, m), 1,94-2,12 (1 H, m), 2,12-2,36 (4 H, m), 3,51-3,69 (1 H, m), 3,93 (3 H, s), 5,70 (2 H, s), 7,36-7,47 (1 H, m), 7,62-7,72 (1 H, m), 8,00 (1 H, s), 8,14-8,32 (3 H, m); This compound was prepared using the procedures described in Example 1, steps a), b) and c) using 3-fluorobenzhydrazide instead of 2-fluorobenzhydrazide in step b). Data for the title compound:<*>H-NMR (250 MHz, d6-DMS0) 6 1.74-1.90 (1 H, m), 1.94-2.12 (1 H, m), 2.12 -2.36 (4 H, m), 3.51-3.69 (1 H, m), 3.93 (3 H, s), 5.70 (2 H, s), 7.36-7 .47 (1 H, m), 7.62-7.72 (1 H, m), 8.00 (1 H, s), 8.14-8.32 (3 H, m);

MS (ES<+>) m/e 380 [MH]<+>. MS (ES<+>) m/e 380 [MH]<+>.

Eksempel 4 Example 4

7- syklobutyl- 3-( 4- fluorfenyl)-6-( 2- metyl- 2H- l, 2, 4- triazol- 3-ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 4- fluorophenyl)-6-( 2- methyl- 2H- 1, 2, 4- triazol- 3-ylmethoxy)- 1, 2, 4- triazolo[ 4, 3-b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyrene beskrevet i eksempel 1, trinn a), b) og c) under anvendelse av 4-fluorbenzhydrazid i stedet for 2-fluorbenzhydrazid i trinn b). Data for tittelforbindelsen:<X>H-NMR (250 MHz, d6-DMS0) 5 1,98-2,12 (1 H, m), 2,18-2,32 (1 H, m), 2,32-2,55 (4 H, m), 3,72-3,90 (1 H, m), 4,17 (3 H, s), 5,90 (2 H, s), 7,62-7,76 (2 H, m), 8,27 (1 H, s), 8,40 (1 H, s), 8,64-8,74 (2 H, m); This compound was prepared using the procedures described in Example 1, steps a), b) and c) using 4-fluorobenzhydrazide instead of 2-fluorobenzhydrazide in step b). Data for the title compound:<X>H-NMR (250 MHz, d6-DMS0) δ 1.98-2.12 (1 H, m), 2.18-2.32 (1 H, m), 2.32 -2.55 (4 H, m), 3.72-3.90 (1 H, m), 4.17 (3 H, s), 5.90 (2 H, s), 7.62-7 .76 (2H, m), 8.27 (1H, s), 8.40 (1H, s), 8.64-8.74 (2H, m);

MS (ES<*>) m/e 380 [MH]\ MS (ES<*>) m/e 380 [MH]\

Eksempel 5 Example 5

7- syklobutyl- 3-( 2, 4- difluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol-3- ylmetoksy)- 1f 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 2, 4- difluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol-3- ylmethoxy)- 1f 2, 4- triazolo[ 4, 3- b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyrene beskrevet i eksempel 1, trinn a), b) og c) under anvendelse av 2,4-difluorbenzhydrazid i stedet for 2-fluorbenzhydrazid i trinn b). Data for tittelforbindelsen:<1>H-NMR (250 MHz, d6-DMS0) 8 1,72-1,90 (1 H, m), 1,90-2,12 (1 H, m), 2,12-2,36 (4 H, m), 3,50-3,68 (1 H, m), 3,82 This compound was prepared using the procedures described in Example 1, steps a), b) and c) using 2,4-difluorobenzhydrazide instead of 2-fluorobenzhydrazide in step b). Data for the title compound:<1>H-NMR (250 MHz, d6-DMS0) 8 1.72-1.90 (1 H, m), 1.90-2.12 (1 H, m), 2.12 -2.36 (4 H, m), 3.50-3.68 (1 H, m), 3.82

(3 H, s), 5,50 (2 H, s), 7,30-7,42 (1 H, m), 7,52-7,64 (1 H, m), 7,93-8,12 (2 H, m), 8,20 (1 H, s); (3 H, s), 5.50 (2 H, s), 7.30-7.42 (1 H, m), 7.52-7.64 (1 H, m), 7.93-8 .12 (2 H, m), 8.20 (1 H, s);

MS (ES<*>) m/e 398 [MH]<*>. MS (ES<*>) m/e 398 [MH]<*>.

Eksempel 6 Example 6

7- syklobutyl- 3-( 3, 5- difluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol-3- ylmetoksy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 3, 5- difluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol-3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

a) 3- klor- 4- syklobutyl- 6- hydrazinopyrldazln 3,6-diklor-4-syklobutylpyridazin (10 g, 0,049 mol) og a) 3-chloro-4-cyclobutyl-6-hydrazinopyrldazln 3,6-dichloro-4-cyclobutylpyridazine (10 g, 0.049 mol) and

hydrazinhydrat (14 ml, 0,30 mol) ble oppvarmet til tilbake-løpskoking i 125 ml dioksan i 24 t. Etter avkjøling krystalliserte den ønskede isomer fra reaksjonsblandingen og ble oppsamlet ved filtrering (4,8 g, 49 %). hydrazine hydrate (14 mL, 0.30 mol) was heated to reflux in 125 mL of dioxane for 24 h. After cooling, the desired isomer crystallized from the reaction mixture and was collected by filtration (4.8 g, 49%).

^-NMR (250 MHz, d6-DMS0) 8 1,68-1,86 (1 H, m), 2,00-2,11 (3 H, m), 2,29-2,38 (2 H, ra), 3,52-3,61 (1 H, m), 4,35 ^-NMR (250 MHz, d6-DMS0) 8 1.68-1.86 (1 H, m), 2.00-2.11 (3 H, m), 2.29-2.38 (2 H , ra), 3.52-3.61 (1 H, m), 4.35

(2 H, br), 6,99 (1 H, s), 8,06 (1 H, br); (2 H, br), 6.99 (1 H, s), 8.06 (1 H, br);

MS (ES<*>) m/e 198 [MH]<+>, 200 [MH]<+.>MS (ES<*>) m/e 198 [MH]<+>, 200 [MH]<+.>

b) N-( 6- klor- 5- syklobutylpyridazin- 3- yl)- N'-( 3, 5- di-fluorbenzyliden) hydrazin b) N-(6-chloro-5-cyclobutylpyridazin-3-yl)-N'-(3,5-difluorobenzylidene)hydrazine

3-klor-4-syklobutyl-6-hydrazinopyridazin (0,502 g, 2,53 mmol) og 3,5-difluorbenzaldehyd (285 ml, 2,78 mmol) ble omrørt i 10 ml 0,2 M saltsyre i 2 t. Dette produkt ble deretter oppsamlet ved filtrering og ble tørket (0,81 g, 99 %). 3-Chloro-4-cyclobutyl-6-hydrazinopyridazine (0.502 g, 2.53 mmol) and 3,5-difluorobenzaldehyde (285 mL, 2.78 mmol) were stirred in 10 mL of 0.2 M hydrochloric acid for 2 h. This product was then collected by filtration and dried (0.81 g, 99%).

MS (ES<*>) 323 [MH]<*>, 325 [MH]<*.>MS (ES<*>) 323 [MH]<*>, 325 [MH]<*.>

c) 6- klor- 7- syklobutyl- 3-( 3, 5- difluorfenyl)- 1, 2, 4- triazolo [ 4, 3- b] pyridazin c) 6- chloro- 7- cyclobutyl- 3-( 3, 5- difluorophenyl)- 1, 2, 4- triazolo [ 4, 3- b] pyridazine

Jern(III)klorid (3,423 g, 12,66 mmol) i 15 ml etanol ble dråpevis tilsatt til en løsning av N-( 6-klor-5-syklobutylpyridazin-3-yl)-N'-(3,5-difluorbenzyliden)hydrazln (0,816 g, 2,53 mmol) i 35 ml etanol og ble oppvarmet til 70 °C. Etter 3 t ble reaksjonsblandingen fordelt mellom 250 ml diklormetan og 250 ml saltvann. Den organiske fase ble tørket (MgS04), ble filtrert og fordampet. Residuet ble renset ved kromatografi på silikagel og ble eluert med etylacetat-heksanblandinger under dannelse av tittelpyridazin (0,51 g, 63 %). Ferric chloride (3.423 g, 12.66 mmol) in 15 mL of ethanol was added dropwise to a solution of N-(6-chloro-5-cyclobutylpyridazin-3-yl)-N'-(3,5-difluorobenzylidene )hydrazln (0.816 g, 2.53 mmol) in 35 mL of ethanol and was heated to 70 °C. After 3 h, the reaction mixture was partitioned between 250 ml dichloromethane and 250 ml brine. The organic phase was dried (MgSO 4 ), filtered and evaporated. The residue was purified by chromatography on silica gel and was eluted with ethyl acetate-hexane mixtures to give the title pyridazine (0.51 g, 63%).

<1>H-NMR (250 MHz, CDC13) 1,84-2,08 (1 H, m), 2,08-2,36 (3 H, m), 2,42-2,68 (2 H, m), 3,65-3,87 (1 H, m), 6,88-7,06 <1>H-NMR (250 MHz, CDCl 3 ) 1.84-2.08 (1 H, m), 2.08-2.36 (3 H, m), 2.42-2.68 (2 H , m), 3.65-3.87 (1 H, m), 6.88-7.06

(1 H, m), 8,01 (1 H, s), 8,04-8,21 (2 H, m); (1H, m), 8.01 (1H, s), 8.04-8.21 (2H, m);

MS (ES<*>) 321 [MH]<*>, 323 [MH]<*>. MS (ES<*>) 321 [MH]<*>, 323 [MH]<*>.

d) 7- syklobutyl- 3-( 3, 5- di fluorfenyl)- 6-( 2- metyl-2H-1, 2, 4- triazol- 3- ylmetoksy)- 1, 2, 4- triazolo[ 4, 3- b]-pyridazin d) 7- cyclobutyl- 3-( 3, 5- difluorophenyl)- 6-( 2- methyl-2H-1, 2, 4- triazol- 3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3 - b]-pyridazine

Til en løsning av (2-metyl-2H-l,2,4-triazol-3-yl)-metanol (0,099 g, 0,879 mmol) (fremstilt under anvendelse av betingelsene beskrevet i EP-A-421210) i 15 ml DMF ble det tilsatt natriumhydrid (0,035 g av en 60 % dispersjon i olje, To a solution of (2-methyl-2H-1,2,4-triazol-3-yl)-methanol (0.099 g, 0.879 mmol) (prepared using the conditions described in EP-A-421210) in 15 mL of DMF sodium hydride (0.035 g of a 60% dispersion in oil,

1,1 mol ekvivalenter) og reaksj onsblandingen ble omrørt ved romtemperatur i 30 min. Etter denne periode ble det foregående produkt (0,256 g, 0,799 mmol) tilsatt som en løsning i 15 ml DMF og reaksjonsblandingen ble omrørt ved romtemperatur i 2 t. Reaksjonsblandingen ble fortynnet med 100 ml vann og den vandige fase ble ekstrahert med 4 x 100 ml diklormetan. De kombinerte ekstrakter ble tørket (Na2S04), ble filtrert og fordampet. Residuet ble renset ved kromatografi på silikagel under anvendelse av 3 % MeOH i diklormetan som elueringsmiddel under dannelse av det ønskede produkt (0,120 g, 38 %). 1.1 mol equivalents) and the reaction mixture was stirred at room temperature for 30 min. After this period, the preceding product (0.256 g, 0.799 mmol) was added as a solution in 15 mL DMF and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with 100 mL water and the aqueous phase was extracted with 4 x 100 mL dichloromethane. The combined extracts were dried (Na 2 SO 4 ), filtered and evaporated. The residue was purified by chromatography on silica gel using 3% MeOH in dichloromethane as eluent to give the desired product (0.120 g, 38%).

<X>H-NMR (360 MHz, CDC13) 1,86-2,02 (1 H, m), 2,08-2,25 (3 H, m), 2,32-2,46 (2 H, m), 3,56-3,70 (1 H, m), 4,01 (3 H, s), 5,64 (2 H, s), 6,92-7,01 (1 H, m), 7,90 (1 H, s), 7,94 <X>H-NMR (360 MHz, CDCl 3 ) 1.86-2.02 (1 H, m), 2.08-2.25 (3 H, m), 2.32-2.46 (2 H , m), 3.56-3.70 (1 H, m), 4.01 (3 H, s), 5.64 (2 H, s), 6.92-7.01 (1 H, m ), 7.90 (1 H, p), 7.94

(1 H, s), 8,03-8,12 (2 H, m); (1H, s), 8.03-8.12 (2H, m);

MS (ES<*>) m/e 398 [MH]<*>. MS (ES<*>) m/e 398 [MH]<*>.

Eksempel 7 Example 7

3-( 2, 4- difluorfenyl)- 7-( 1- metylsyklobutyl)- 6-( 2- metyl- 2H-1, 2, 4- triazol- 3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 3-( 2, 4- difluorophenyl)- 7-( 1- methylcyclobutyl)- 6-( 2- methyl- 2H-1, 2, 4- triazol- 3-ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyrene beskrevet i eksempel 1, trinn a), under anvendelse av 1-metylsyklobutankarboksylsyre (Journal of Organometallic Chemistry, 1988, 352, 263-272) i stedet for syklobutankarboksylsyre, og eksempel 6, trinn a), b), c) og d), under anvendelse av 2,4-difluorbenzaldehyd i stedet for 3,5-difluorbenzaldehyd i trinn b). Data for tittelforbindelsen:<1>H-NMR (360 MHz, CDC13) 1,52 (3 H, s), 1,78-1,92 This compound was prepared using the procedures described in Example 1, step a), using 1-methylcyclobutanecarboxylic acid (Journal of Organometallic Chemistry, 1988, 352, 263-272) instead of cyclobutanecarboxylic acid, and Example 6, step a). b), c) and d), using 2,4-difluorobenzaldehyde instead of 3,5-difluorobenzaldehyde in step b). Data for the title compound:<1>H-NMR (360 MHz, CDCl3) 1.52 (3 H, s), 1.78-1.92

(1 H, m), 2,04-2,26 (3 H, m), 2,34-2,46 (2 H, m), 3,88 (3 H, s), 5,47 (2 H, s), 7,00-7,15 (2 H, m), 7,74 (1 H, s), 7,83-7,93 (2 H, m); (1 H, m), 2.04-2.26 (3 H, m), 2.34-2.46 (2 H, m), 3.88 (3 H, s), 5.47 (2 H, s), 7.00-7.15 (2H, m), 7.74 (1H, s), 7.83-7.93 (2H, m);

MS (ES<+>) m/e 412 [MH]\ MS (ES<+>) m/e 412 [MH]\

Eksempel 8 Example 8

7- syklobutyl- 3-( 3, 4- difluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol-3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyrldazin 7- cyclobutyl- 3-( 3, 4- difluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol-3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyrldazine

Denne forbindelse ble fremstilt under anvendelse av prosedyrene beskrevet i eksempel 1, trinn a), og eksempel 6, trinn a), b), c) og d), under anvendelse av 3,4-difluorbenzaldehyd i stedet for 3,5-difluorbenzaldehyd i trinn b). Data for tittelforbindelsen:<1>H-NMR (360 MHz, CDC13) 8 1,86-2,00 (1 H, m), 2,06-2,24 (3 H, m), 2,30-2,46 (2 H, m), 3,57-3,70 (1 H, m), 4,00 This compound was prepared using the procedures described in Example 1, step a), and Example 6, steps a), b), c) and d), using 3,4-difluorobenzaldehyde instead of 3,5-difluorobenzaldehyde in step b). Data for the title compound:<1>H-NMR (360 MHz, CDC13) 8 1.86-2.00 (1 H, m), 2.06-2.24 (3 H, m), 2.30-2 .46 (2 H, m), 3.57-3.70 (1 H, m), 4.00

(3 H, s), 5,62 (2 H, s), 7,32-7,40 (1 H, m), 7,90 (1 H, s), 7,96 (1 H, s), 8,20-8,80 (1 H, m), 8,32-8,40 (1 H, m); (3 H, s), 5.62 (2 H, s), 7.32-7.40 (1 H, m), 7.90 (1 H, s), 7.96 (1 H, s) , 8.20-8.80 (1H, m), 8.32-8.40 (1H, m);

MS (ES<+>) m/e 398 [MH]\ MS (ES<+>) m/e 398 [MH]\

Eksempel 9 Example 9

7- syklobutyl- 3-( 2, 3- difluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol-3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 2, 3- difluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol-3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyrene beskrevet i eksempel 1, trinn a), og eksempel 6, trinn a), b), c) og d), under anvendelse av 2,3-difluorbenzaldehyd i stedet for 3,5-difluorbenzaldehyd i trinn b). Data for tittelforbindelsen: ^-NMR (360 MHz, CDC13) 8 1,86-1,98 (1 H, m), 2,04-2,24 (3 H, m), 2,30-2,44 (2 H, m), 3,58-3,70 (1 H, m), 3,90 This compound was prepared using the procedures described in Example 1, step a), and Example 6, steps a), b), c) and d), using 2,3-difluorobenzaldehyde instead of 3,5-difluorobenzaldehyde in step b). Data for the title compound: 3-NMR (360 MHz, CDCl 3 ) δ 1.86-1.98 (1 H, m), 2.04-2.24 (3 H, m), 2.30-2.44 ( 2 H, m), 3.58-3.70 (1 H, m), 3.90

(3 H, s), 5,50 (2 H, s), 7,26-7,34 (1 H, m), 7,34-7,46 (1 H, m), 7,62-7,80 (1 H, m), 7,88 (1 H, s), 7,92 (1 H, s); (3 H, s), 5.50 (2 H, s), 7.26-7.34 (1 H, m), 7.34-7.46 (1 H, m), 7.62-7 .80 (1H, m), 7.88 (1H, s), 7.92 (1H, s);

MS (ES<*>) m/e 398 [MH]<*.>MS (ES<*>) m/e 398 [MH]<*.>

Eksempel 10 Example 10

7- syklobutyl- 3-( 2, 6- difluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol-3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 2, 6- difluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol-3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyrene beskrevet i eksempel 1, trinn a), og eksempel 6, trinn a), b), c) og d), under anvendelse av 2,6-difluorbenzaldehyd i stedet for 3,5-difluorbenzaldehyd i trinn b). Data for tittelforbindelsen:<1>H-NMR (360 MHz, CDC13) 8 1,86-1,96 (1 H, m), 2,04-2,24 (3 H, m), 2,30-2,42 (2 H, m), 3,56-3,68 (1 H, m), 3,84 This compound was prepared using the procedures described in Example 1, step a), and Example 6, steps a), b), c) and d), using 2,6-difluorobenzaldehyde instead of 3,5-difluorobenzaldehyde in step b). Data for the title compound:<1>H-NMR (360 MHz, CDCl 3 ) 8 1.86-1.96 (1 H, m), 2.04-2.24 (3 H, m), 2.30-2 .42 (2 H, m), 3.56-3.68 (1 H, m), 3.84

(3 H, s), 5,42 (2 H, s), 7,08-7,16 (2 H, m), 7,55-7,60 (1 H, m), 7,88 (2 H, rn); (3 H, s), 5.42 (2 H, s), 7.08-7.16 (2 H, m), 7.55-7.60 (1 H, m), 7.88 (2 H, rn);

MS (ES<*>) m/e 398 [MH]<*.>MS (ES<*>) m/e 398 [MH]<*.>

Eksempel 11 Example 11

7- syklobutyl- 3-( 2, 5- difluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- trlazol-3- ylmetoksy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 2, 5- difluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- trilazol-3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyrene beskrevet i eksempel 1, trinn a), og eksempel 6, trinn a), b), c) og d), under anvendelse av 2,5-difluorbenzaldehyd i stedet for 3,5-difluorbenzaldehyd i trinn b). Data for tittelforbindelsen: ^-NMR (360 MHz, CDC13) 8 1,86-1,98 (1 H, m), 2,04-2,24 (3 H, m), 2,30-2,46 (2 H, m), 3,56-3,70 (1 H, m), 3,90 This compound was prepared using the procedures described in Example 1, step a), and Example 6, steps a), b), c) and d), using 2,5-difluorobenzaldehyde instead of 3,5-difluorobenzaldehyde in step b). Data for the title compound: 3-NMR (360 MHz, CDCl 3 ) δ 1.86-1.98 (1 H, m), 2.04-2.24 (3 H, m), 2.30-2.46 ( 2 H, m), 3.56-3.70 (1 H, m), 3.90

(3 H, s), 5,48 (2 H, s), 7,20-7,30 (2 H, m), 7,60-7,68 (1 H, m), 7,88 (1 H, s), 7,92 (1 H, s); (3 H, s), 5.48 (2 H, s), 7.20-7.30 (2 H, m), 7.60-7.68 (1 H, m), 7.88 (1 H, s), 7.92 (1 H, s);

MS (ES<*>) m/e 398 [MH]<*>. MS (ES<*>) m/e 398 [MH]<*>.

Eksempel 12 Example 12

3-( 2, 4- difluorfenyl)- 7-( 1- metylsykloheksyl)- 6-( 2- metyl- 2H-1, 2, 4- triazol- 3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 3-( 2, 4- difluorophenyl)- 7-( 1- methylcyclohexyl)- 6-( 2- methyl- 2H-1, 2, 4- triazol- 3-ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

a) 3, 6- diklor- 4-( 1- metylsykloheksyl) pyridazin a) 3,6-dichloro-4-(1-methylcyclohexyl)pyridazine

Konsentrert svovelsyre (10,7 ml, 0,2 mol) ble tilsatt Concentrated sulfuric acid (10.7 mL, 0.2 mol) was added

til en løsning av 3,6-diklorpyridazin (10 g, 67 mmol) i 250 ml vann. Denne blanding ble oppvarmet til 70 °C før tilsetning av 1-metylsykloheksankarboksylsyre (9,67 g, 68 mmol). Sølvnitrat (2,3 g, 13,5 mmol) i 5 ml vann ble deretter tilsatt i løpet av ett minutt, etterfulgt av ammoniumpersulfat (45,6 g, 0,2 mol) i 95 ml vann tilsatt i løpet av 20 min. Etter endt tilsetning ble reaksjonsblandingen omrørt i ytterligere 5 min og fikk deretter avkjøles til romtemperatur. Blandingen ble avkjølt til 0 °C (is/vannbad) og ble gjort basisk med konsentrert vandig ammoniakkløsning (indre temperatur <10 °C). Den vandige fase ble ekstrahert med 3 x 350 ml diklormetan og de kombinerte ekstrakter ble vasket med 350 ml saltvann, ble tørket (MgS04), filtrert og fordampet. Residuet ble renset ved kromatografi på silikagel under anvendelse av 0—>5 % etylacetat i diklormetan som elueringsmiddel under dannelse av det ønskede produkt (5,93 g):<1>H-NMR (250 MHz, CDC13) 8 1,33-1,74 (6 H, m), 1,43 (3 H, s), 1,80-1,96 (2 H, m), 1,97-2,12 (2 H, m), 7,49 (1 H, s); to a solution of 3,6-dichloropyridazine (10 g, 67 mmol) in 250 mL of water. This mixture was heated to 70 °C before addition of 1-methylcyclohexanecarboxylic acid (9.67 g, 68 mmol). Silver nitrate (2.3 g, 13.5 mmol) in 5 mL water was then added over one minute, followed by ammonium persulfate (45.6 g, 0.2 mol) in 95 mL water added over 20 min. After the addition was complete, the reaction mixture was stirred for a further 5 min and was then allowed to cool to room temperature. The mixture was cooled to 0 °C (ice/water bath) and basified with concentrated aqueous ammonia solution (internal temperature <10 °C). The aqueous phase was extracted with 3 x 350 ml of dichloromethane and the combined extracts were washed with 350 ml of brine, dried (MgSO 4 ), filtered and evaporated. The residue was purified by chromatography on silica gel using 0->5% ethyl acetate in dichloromethane as eluent to give the desired product (5.93 g):<1>H-NMR (250 MHz, CDCl 3 ) 8 1.33- 1.74 (6 H, m), 1.43 (3 H, s), 1.80-1.96 (2 H, m), 1.97-2.12 (2 H, m), 7, 49 (1 H, p);

MS (ES<+>) m/e 249 [MH]\ 247 [MH]<*>, 245 [MH]\ MS (ES<+>) m/e 249 [MH]\ 247 [MH]<*>, 245 [MH]\

b) 6- klor- 3-( 2, 4- difluorfenyl)- 7-( 1- metylsykloheksyl) - 1, 2, 4- triazolo[ 4, 3- b] pyridazin b) 6- chloro- 3-( 2, 4- difluorophenyl)- 7-( 1- methylcyclohexyl)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

En blanding av 3,6-diklor-4-(1-metylsykloheksyl)-pyridazin (1,29 g, 5,27 mmol), 2,4-difluorbenzosyrehydrazid (1,72 g, 10 mmol) og trietylaminhydroklorid (1,09 g, 7,9 mmol) i 5 ml p-xylen ble omrørt og oppvarmet til tilbakeløpskoking i 24 t. Etter avkjøling ble de flyktige bestanddeler fjernet i vakuum, og residuet ble fordelt mellom 100 ml diklormetan og 100 ml vann og 100 ml NaHC03. Uoppløst, fast materiale ble fjernet ved filtrering. Lagene ble separert, og det vandige lag ble ytterligere ekstrahert med 2 x 100 ml diklormetan. De kombinerte, organiske ekstrakter ble tørket (MgS04), ble fil trert og fordampet. Residuet ble renset ved kromatografi på silika og eluert med 0 %->25 % etylacetat i diklormetan under dannelse av det ønskede produkt (0,74 g):<1>H-NMR (250 MHz, CDC13) 6 1,34-1,74 (6 H, m), 1,50 A mixture of 3,6-dichloro-4-(1-methylcyclohexyl)-pyridazine (1.29 g, 5.27 mmol), 2,4-difluorobenzoic acid hydrazide (1.72 g, 10 mmol) and triethylamine hydrochloride (1.09 g, 7.9 mmol) in 5 ml p-xylene was stirred and heated to reflux for 24 h. After cooling, the volatiles were removed in vacuo and the residue was partitioned between 100 ml dichloromethane and 100 ml water and 100 ml NaHCO 3 . Undissolved solid material was removed by filtration. The layers were separated and the aqueous layer was further extracted with 2 x 100 ml of dichloromethane. The combined organic extracts were dried (MgSO 4 ), filtered and evaporated. The residue was purified by chromatography on silica and eluted with 0%->25% ethyl acetate in dichloromethane to give the desired product (0.74 g): <1>H-NMR (250 MHz, CDCl3) 6 1.34-1 .74 (6 H, m), 1.50

(3 H, s), 1,90-2,15 (4 H, m), 7,01-7,14 (2 H, m), 7,87-7,98 (3 H, s), 1.90-2.15 (4 H, m), 7.01-7.14 (2 H, m), 7.87-7.98

(1 H, m), 8,18 (1 H, s); (1 H, m), 8.18 (1 H, s);

MS (ES<+>) m/e 365 [MH]<+>, 363 [MH]<+>. MS (ES<+>) m/e 365 [MH]<+>, 363 [MH]<+>.

c) 3-( 2, 4- difluorfenyl)- 7-( 1- metylsykloheksyl)- 6-( 2-metyl- 2H- l, 2, 4- triazol- 3- ylmetoksy)- 1, 2, 4- triazolo-[ 4, 3- b] pyridazin c) 3-( 2, 4- difluorophenyl)- 7-( 1- methylcyclohexyl)- 6-( 2-methyl- 2H- 1, 2, 4- triazol- 3-ylmethoxy)- 1, 2, 4- triazolo- [4,3-b]pyridazine

Natriumhydrid (60 % dispersjon i olje, 13 mg, Sodium hydride (60% dispersion in oil, 13 mg,

0,33 mmol) ble tilsatt til en omrørt løsning av (2-metyl-2H-1,2,4-triazol-3-yl)metanol (fremstilt under anvendelse av betingelsene beskrevet i EF-A-421210; 37 mg, 0,33 mmol) i 5 ml vannfri N,N-dimetylformamid ved romtemperatur under nitrogen. Dette ble omrørt i 30 min og 6-klor-3-(2,4-difluorfenyl)-7-(1-metylsykloheksyl)-l,2,4-triazolo[4,3-b]pyridazin (100 mg, 0,275 mmol) i 3 ml N,N-dimetylformamid ble deretter tilsatt og blandingen ble omrørt i ytterligere 60 min. Reaksjonen ble stanset med 20 ml vann og blandingen ble omrørt i ytterligere 60 min. Det utfelte, faste materialet ble oppsamlet ved filtrering og ble vasket med vann. Det faste materialet ble opp-løst i 20 ml diklormetan, ble filtrert og fordampet. Residuet ble omkrystallisert fr etylacetat/heksan under dannelse av tittelforbindelsen (38 mg): smp.: = 196 °C; 0.33 mmol) was added to a stirred solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (prepared using the conditions described in EF-A-421210; 37 mg, 0 .33 mmol) in 5 ml of anhydrous N,N-dimethylformamide at room temperature under nitrogen. This was stirred for 30 min and 6-chloro-3-(2,4-difluorophenyl)-7-(1-methylcyclohexyl)-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.275 mmol ) in 3 ml of N,N-dimethylformamide was then added and the mixture was stirred for a further 60 min. The reaction was quenched with 20 ml of water and the mixture was stirred for a further 60 min. The precipitated solid material was collected by filtration and washed with water. The solid material was dissolved in 20 ml of dichloromethane, filtered and evaporated. The residue was recrystallized from ethyl acetate/hexane to give the title compound (38 mg): mp: = 196 °C;

^i-NMR (360 MHz, CDC13) 1,32 (3 H, s), 1,33-1,66 η-NMR (360 MHz, CDCl 3 ) 1.32 (3 H, s), 1.33-1.66

(6 H, m), 1,72-1,81 (2 H, m), 1,93-2,03 (2 H, m), 3,87 (3 H, s), 5,50 (2 H, s), 7,00-7,14 (2 H, m), 7,83-7,90 (1 H, m), 7,91 (1 H, s), 8,00 (1 H, s); (6 H, m), 1.72-1.81 (2 H, m), 1.93-2.03 (2 H, m), 3.87 (3 H, s), 5.50 (2 H, s), 7.00-7.14 (2 H, m), 7.83-7.90 (1 H, m), 7.91 (1 H, s), 8.00 (1 H, s);

MS (ES<+>) m/e 440 [MH]<*>; MS (ES<+>) m/e 440 [MH]<*>;

Analyse funnet: C 59,74, H 5,23, N 22,10 Analysis found: C 59.74, H 5.23, N 22.10

C22H23FjN70 kreves: C 60,13, H 5,27, N 22,31 %. C22H23FjN70 required: C 60.13, H 5.27, N 22.31%.

Eksempel 13 Example 13

3-( 2, 4- difluorfenyl)-7-( 1- metylsykloheksyl)- 6-( 1- metyl- lH-1, 2, 4- triazol- 3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin Denne forbindelse ble fremstilt under anvendelse av 3-( 2, 4- difluorophenyl)-7-( 1- methylcyclohexyl)- 6-( 1- methyl- 1H-1, 2, 4- triazol- 3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine This compound was prepared using

prosedyren beskrevet i eksempel 12, trinn c), med (1-metyl-lH-1,2,4-triazol-3-yl)metanol (fremstilt under anvendelse av betingelsene beskrevet i EP-A-421210) i stedet for (2-metyl-2H-1,2,4-triazol-3-yl)metanol. Data for tittelforbindelsen: smp. = 156 °C; the procedure described in Example 12, step c), with (1-methyl-1H-1,2,4-triazol-3-yl)methanol (prepared using the conditions described in EP-A-421210) in place of (2 -methyl-2H-1,2,4-triazol-3-yl)methanol. Data for the title compound: m.p. = 156 °C;

<1>H-NMR (360 MHz, CDC13) 8 1,36 (3 H, s), 1,37-1,66 <1>H-NMR (360 MHz, CDCl 3 ) 8 1.36 (3 H, s), 1.37-1.66

(6 H, m), 1,74-1,84 (2 H, m), 1,99-2,10 (2 H, m), 3,93 (3 H, s), 5,44 (2 H, s), 6,99-7,11 (2 H, m), 7,96 (1 H, s), 7,97-8,03 (1 H, m), 8,04 (1 H, s); (6 H, m), 1.74-1.84 (2 H, m), 1.99-2.10 (2 H, m), 3.93 (3 H, s), 5.44 (2 H, s), 6.99-7.11 (2 H, m), 7.96 (1 H, s), 7.97-8.03 (1 H, m), 8.04 (1 H, s);

MS (ES<+>) m/e 440 [MH]<+>; MS (ES<+>) m/e 440 [MH]<+>;

Analyse funnet: C 60,48, H 5,08, N 22,39 Analysis found: C 60.48, H 5.08, N 22.39

C22H23F2N70 kreves: C 60,13, H 5,27, N 22,31 %. C22H23F2N70 required: C 60.13, H 5.27, N 22.31%.

Eksempel 14 Example 14

7- syklobutyl- 3-( 2- fluorfenyl)- 6-( 1- metyl- lH- pyrazol- 3- yl-metoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 2- fluorophenyl)- 6-( 1- methyl- 1H- pyrazol- 3- yl- methoxy)- 1, 2, 4- triazolo[ 4, 3-b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyren beskrevet i eksempel 1, trinn c), med (1-metyl-1H-pyrazol-3-yl)metanol (fremstilt under anvendelse av betingelsene beskrevet i EP-A-91130) anvendt i stedet for (2-metyl-2H-1,2,4-triazol-3-yl)metanol. Data for tittelforbindelsen: smp. = 184-186 °C; This compound was prepared using the procedure described in Example 1, step c), with (1-methyl-1H-pyrazol-3-yl)methanol (prepared using the conditions described in EP-A-91130) used instead of (2-methyl-2H-1,2,4-triazol-3-yl)methanol. Data for the title compound: m.p. = 184-186 °C;

<1>H-NMR (360 MHz, DMSO) 8 1,80 (1 H, m), 1,99 (1 H, m), 2,18 (4 H, m), 3,55 (1 H, m), 3,82 (3 H, s), 5,23 (2 H, s), 6,25 (1 H, s), 7,44-7,51 (2 H, m), 7,65 (2 H, m), 7,99 <1>H-NMR (360 MHz, DMSO) 8 1.80 (1 H, m), 1.99 (1 H, m), 2.18 (4 H, m), 3.55 (1 H, m), 3.82 (3 H, s), 5.23 (2 H, s), 6.25 (1 H, s), 7.44-7.51 (2 H, m), 7.65 (2 H, m), 7.99

(1 H, m), 8,18 (1 H, s); (1 H, m), 8.18 (1 H, s);

MS (ES<+>) m/e 379 [MH]\ MS (ES<+>) m/e 379 [MH]\

Analyse funnet: C 62,81, H 4,69, N 21,68 C20HigFN6O-0,2 Hz0 kreves: C 62,88, H 5,12, N 22,00 %. Analysis found: C 62.81, H 4.69, N 21.68 C 20 HigFN 6 O-0.2 Hz0 required: C 62.88, H 5.12, N 22.00%.

Eksempel 15 Example 15

7- syklobutyl- 3-( 2- fluorfenyl)- 6-( 5- metylisoksazol- 3- yl-metoksy)- l, 2, 4- trlazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 2- fluorophenyl)- 6-( 5- methylisoxazol- 3- yl-methoxy)- 1, 2, 4- trlazolo[ 4, 3-b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyren beskrevet i eksempel 1, trinn c), med (5-metylisoksazol-3-yl)metanol i stedet for (2-metyl-2H-l,2,4-triazol-3-yl)metanol. Data for tittelforbindelsen: smp. = 150 °C; This compound was prepared using the procedure described in Example 1, step c), with (5-methylisoxazol-3-yl)methanol in place of (2-methyl-2H-1,2,4-triazol-3-yl) methanol. Data for the title compound: m.p. = 150 °C;

<X>H-NMR (360 MHz, CDC13) 8 1,92 (1 H, m), 2,16 (3 H, m), 2,40 (2 H, m), 2,44 (3 H, s), 3,63 (1 H, m), 5,36 (2 H, s), 6,01 (1 H, s), 7,25-7,36 (2 H, m), 7,55 (1 H, m), 7,82 <X>H-NMR (360 MHz, CDC13) 8 1.92 (1 H, m), 2.16 (3 H, m), 2.40 (2 H, m), 2.44 (3 H, s), 3.63 (1 H, m), 5.36 (2 H, s), 6.01 (1 H, s), 7.25-7.36 (2 H, m), 7.55 (1 H, m), 7.82

(1 H, s), 7,89 (1 H, rn); (1H, s), 7.89 (1H, rn);

MS (ES<*>) m/e 380 [MH]<*>; MS (ES<*>) m/e 380 [MH]<*>;

Analyse funnet: C 62,99, H 4,74, N 18,09 Analysis found: C 62.99, H 4.74, N 18.09

C20H18FNsO kreves: C 63,32, H 4,74, N 18,46 %. C20H18FNsO required: C 63.32, H 4.74, N 18.46%.

Eksempel 16 Example 16

7- syklobutyl- 3-( 2- fluorfenyl)- 6-( l- metyl- lH- imidazol- 2- yl-metoksy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 2- fluorophenyl)- 6-( 1- methyl- 1H- imidazol- 2- yl- methoxy)- 1, 2, 4- triazolo[ 4, 3-b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyren beskrevet i eksempel 1, trinn c), med (1-metyl-lH-imidazol-2-yl)metanol i stedet for (2-metyl-2H-l,2,4-triazol-3-yl)metanol. Data for tittelforbindelsen: smp. = 173 °C; This compound was prepared using the procedure described in Example 1, step c), with (1-methyl-1H-imidazol-2-yl)methanol in place of (2-methyl-2H-1,2,4-triazol- 3-yl)methanol. Data for the title compound: m.p. = 173 °C;

<X>H-NMR (360 MHz, CDC13) 5 1,89 (1 H, m), 2,10 (3 H, m), 2,32 (2 H, m), 3,61 (1 H, m), 3,65 (3 H, s), 5,40 (2 H, s), 6,94 (1 H, s), 7,06 (1 H, s), 7,26-7,36 (2 H, m), 7,55 <X>H-NMR (360 MHz, CDCl 3 ) δ 1.89 (1 H, m), 2.10 (3 H, m), 2.32 (2 H, m), 3.61 (1 H, m), 3.65 (3 H, s), 5.40 (2 H, s), 6.94 (1 H, s), 7.06 (1 H, s), 7.26-7.36 (2 H, m), 7.55

(1 H, m), 7,82 (1 H, s), 7,92 (1 H, m); (1 H, m), 7.82 (1 H, s), 7.92 (1 H, m);

MS (ES<*>) m/e 379 [MH]<*>. MS (ES<*>) m/e 379 [MH]<*>.

Eksempel 17 Example 17

7- syklobutyl- 3-( 2- fluorfenyl)- 6-( 4- metyl- 4H- l, 2, 4- triazol- 3-ylmetoksy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 2- fluorophenyl)- 6-( 4- methyl- 4H- 1, 2, 4- triazol- 3-ylmethoxy)- 1, 2, 4- triazolo[ 4, 3-b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyren beskrevet i eksempel 1, trinn c), med (4-metyl-4H-l,2,4-triazol-3-yl)metanol i stedet for (2-metyl-2H-l,2,4-triazol-3-yl)metanol. Data for tittelforbindelsen: smp. = 228 °C; This compound was prepared using the procedure described in Example 1, step c), with (4-methyl-4H-1,2,4-triazol-3-yl)methanol in place of (2-methyl-2H-1, 2,4-triazol-3-yl)methanol. Data for the title compound: m.p. = 228 °C;

<1>H-NMR (360 MHz, CDC13) 8 1,91 (1 H, m), 2,10 (3 H, m), 2,32 (2 H, m), 3,56 (1 H, m), 3,71 (3 H, s), 5,54 (2 H, s), 7,25-7,37 (2 H, m), 7,56 (1 H, m), 7,85 (1 H, s), 7,89 <1>H-NMR (360 MHz, CDCl3) 8 1.91 (1 H, m), 2.10 (3 H, m), 2.32 (2 H, m), 3.56 (1 H, m), 3.71 (3 H, s), 5.54 (2 H, s), 7.25-7.37 (2 H, m), 7.56 (1 H, m), 7.85 (1 H, p), 7.89

(1 H, m), 8,18 (1 H, s); (1 H, m), 8.18 (1 H, s);

MS (ES<*>) m/e 380 [MH]<*>. MS (ES<*>) m/e 380 [MH]<*>.

Analyse funnet: C 59,70, H 4,74, N 25,50 Analysis found: C 59.70, H 4.74, N 25.50

C19H18FN60 kreves: C 60,15, H 4,78, N 25,84 %. C19H18FN60 required: C 60.15, H 4.78, N 25.84%.

Eksempel 18 Example 18

3- ( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol- 3- ylmetoksy)- 7-( tien- 2- yl)- 1, 2, 4- triazolo[ 4 r3 - b] pyridazin- 0, 9 hydrat 3-( 2- fluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol- 3- ylmethoxy)- 7-( thien- 2- yl)- 1, 2, 4- triazolo[ 4 r3 - b] pyridazine- 0.9 hydrate

a) 4- brom- l, 2- dihydropyridazin- 3/ 6- dion a) 4-bromo-1,2-dihydropyridazine-3/6-dione

Hydrazinhydrat (28 ml, 576 mmol) ble dråpevis tilsatt Hydrazine hydrate (28 mL, 576 mmol) was added dropwise

til en omrørt løsning av brommalinsyreanhydrid (100 g, to a stirred solution of bromalic anhydride (100 g,

565 mmol) ill THF avkjølt i et isbad slik at den indre temperatur ikke overskred 10 °C. Etter endt tilsetning av hydra-zinet ble blandingen kokt under tilbakeløpskjøling i 18 t. Løsningsmidlet ble fjernet ved fordampning og residuet ble tørket ved azeotrop behandling med toluen. Residuet ble tri-turert og vasket med dietyleter under dannelse av tittelforbindelsen som et orange, fast materiale (83 g, 77 %).<1>H-NMR (250 MHz, d6-DMS0) 5 7,68 (1 H, br s). MS (ES<*>) m/e 193 [MH]<+>, 191 [MH]<+>. Dette materialet ble anvendt uten ytterligere rensing. 565 mmol) in THF cooled in an ice bath so that the internal temperature did not exceed 10 °C. After the addition of the hydrazine was finished, the mixture was boiled under reflux for 18 h. The solvent was removed by evaporation and the residue was dried by azeotropic treatment with toluene. The residue was triturated and washed with diethyl ether to give the title compound as an orange solid (83 g, 77%). s). MS (ES<*>) w/e 193 [MH]<+>, 191 [MH]<+>. This material was used without further purification.

b) 3, 6- diklor- 4-( tien- 2- yl) pyridazin b) 3,6-dichloro-4-(thien-2-yl)pyridazine

En blanding av 4-brom-l,2-dihydropyridazin-3,6-dion A mixture of 4-bromo-1,2-dihydropyridazine-3,6-dione

(9 g, 47 mmol), 2-tiofenborsyre (7 g, 55 mmol), natriumkarbo-nat (11,7 g, 110 mmol) og 5 g tetrakis(trifenylfosfin)palladium(0) i 250 ml DME og 100 ml vann ble avgasset, ble spylt med nitrogen og tilbakeløpskokt i 18 t. Løsningsmidlet ble fjernet ved fordampning og residuet ble behandlet azeotropt med toluen. Det resulterende, faste materialet ble fortynnet med 20 ml diklormetan og 70 ml fosforoksyklorid og ble kokt under til-bakeløpskjøling i 4 t. Reaksjonsblandingen ble avkjølt, ble langsomt tilsatt til isvann, ble gjort basisk med vandig natriumhydrogenkarbonat og ble ekstrahert med diklormetan. Det organiske lag ble tørket (Na2S04), ble filtrert og konsentrert. Tørrflashkolonnekromatografi og eluering med 30 % etylacetatheksan, ga tittelforbindelsen som et orange, fast materiale (1,18 g, 11 %). (9 g, 47 mmol), 2-thiophenboronic acid (7 g, 55 mmol), sodium carbonate (11.7 g, 110 mmol) and 5 g of tetrakis(triphenylphosphine)palladium(0) in 250 ml DME and 100 ml water was degassed, flushed with nitrogen and refluxed for 18 h. The solvent was removed by evaporation and the residue was azeotroped with toluene. The resulting solid was diluted with 20 mL of dichloromethane and 70 mL of phosphorus oxychloride and refluxed for 4 h. The reaction mixture was cooled, slowly added to ice water, basified with aqueous sodium bicarbonate, and extracted with dichloromethane. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. Dry flash column chromatography eluting with 30% ethyl acetate hexane gave the title compound as an orange solid (1.18 g, 11%).

<1>H-NMR (360 MHz, CDC13) 8 7,24 (1 H, dd, J 5 og <1>H-NMR (360 MHz, CDC13) 8 7.24 (1 H, dd, J 5 and

4 Hz), 7,65-7,68 (2 H, m), 7,80 (1 H, dd, J 4 og 1 Hz). 4 Hz), 7.65-7.68 (2 H, m), 7.80 (1 H, dd, J 4 and 1 Hz).

MS (ES<*>) m/e 231 [MH]<*>, 233 [MH]<*>, 235 [MH]<*>. MS (ES<*>) m/e 231 [MH]<*>, 233 [MH]<*>, 235 [MH]<*>.

c) 6-klor-3-( 2- fluorfenyl)- 7- ( tien- 2- yl)- 1, 2, 4- triazolo-[ 4, 3- b] pyridazin c) 6-chloro-3-(2-fluorophenyl)-7-(thien-2-yl)-1,2,4-triazolo-[4,3-b]pyridazine

En blanding av 3,6-diklor-4-(tien-2-yl)pyridazin erholdt ovenfor (0,5 g, 2,1 mmol), 2-fluorbenzhydrazid (0,66 g, 4,3 mmol) og trietylaminhydroklorid (0,59 g, 4,3 mmol) i 10 ml p-xylen ble omrørt og oppvarmet til tilbakeløpskoking under nitrogen i 30 t. Etter avkjøling ble de flyktige bestanddeler fjernet i vakuum. Residuet ble delvis renset ved kromatografi på silikagel og eluering med 50 %->66 %->100 % etylacetatheksan under dannelse av tittelforbindelsen som et gult, fast materiale (0,19 g, 26 %). MS (ES<*>) m/e 331 [MH]\ 333 [MH]\ Dette materialet ble anvendt uten ytterligere rensing. A mixture of 3,6-dichloro-4-(thien-2-yl)pyridazine obtained above (0.5 g, 2.1 mmol), 2-fluorobenzhydrazide (0.66 g, 4.3 mmol) and triethylamine hydrochloride ( 0.59 g, 4.3 mmol) in 10 ml of p-xylene was stirred and heated to reflux under nitrogen for 30 h. After cooling, the volatiles were removed in vacuo. The residue was partially purified by chromatography on silica gel eluting with 50%->66%->100% ethyl acetate-hexane to give the title compound as a yellow solid (0.19 g, 26%). MS (ES<*>) m/e 331 [MH]\ 333 [MH]\ This material was used without further purification.

d) 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol- 3- yl-metoksy)- 7-( tien- 2- yl)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin ' 0, 9 hydrat d) 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-yl-methoxy)-7-(thien-2-yl)-1,2,4- triazolo[4,3-b]pyridazine' 0,9 hydrate

Til en løsning av (2-metyl-2H-l,2,4-triazol-3-yl)-metanol (0,11 g, 1,0 mmol) (fremstilt under betingelsene beskrevet i EP-A-421210) i 5 ml DMF ble det tilsatt natriumhydrid (0,04 g av en 60 % dispersjon i olje, 1 mol ekvivalent) og reaksjonsblandingen ble omrørt ved romtemperatur i 30 min. Ved dette tidspunkt ble 6-klor-3-(2-fluorfenyl)-7-(tien-2-yl)-l,2,4-triazolo[4,3-b]pyridazin (0,19 g, 0,57 mmol) tilsatt og reaksjonsblandingen ble omrørt ved romtemperatur i 18 t. Reaksjonsblandingen ble fortynnet med 70 ml vann og det utfelte materialet ble oppsamlet. Det faste materialet ble renset ved kokning i etylacetat og oppsamling av tittelforbindelsen som et gult, fast materiale (0,01 g, 12 %). To a solution of (2-methyl-2H-1,2,4-triazol-3-yl)-methanol (0.11 g, 1.0 mmol) (prepared under the conditions described in EP-A-421210) in 5 ml of DMF was added sodium hydride (0.04 g of a 60% dispersion in oil, 1 mol equivalent) and the reaction mixture was stirred at room temperature for 30 min. At this point, 6-chloro-3-(2-fluorophenyl)-7-(thien-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (0.19 g, 0.57 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with 70 ml of water and the precipitated material was collected. The solid was purified by boiling in ethyl acetate and collecting the title compound as a yellow solid (0.01 g, 12%).

<1>H-NMR (250 MHz, d6-DMS0) 8 3,83 (3 H, s), 5,64 (2 H, s), 7,24 (1 H, dd, J 4 og 4 Hz), 7,44-7,55 (2 H, m), 7,66-7,71 (1 H, m), 7,82 (1 H, d, J 5 Hz), 7,96-8,01 (3 H, m), 8,23 <1>H-NMR (250 MHz, d6-DMS0) 8 3.83 (3 H, s), 5.64 (2 H, s), 7.24 (1 H, dd, J 4 and 4 Hz) , 7.44-7.55 (2 H, m), 7.66-7.71 (1 H, m), 7.82 (1 H, d, J 5 Hz), 7.96-8.01 (3 H, m), 8.23

(1 H, s); (1H, s);

MS (ES<*>) m/e 408 [MH]<*>; MS (ES<*>) m/e 408 [MH]<*>;

Analyse funnet: C 53,81, H 3,62, N 23,42 % C19H14FN7OS-0,9 (Hj.0) kreves: C 53,87, H 3,76, N 23,14 % Analysis found: C 53.81, H 3.62, N 23.42% C19H14FN7OS-0.9 (Hj.0) required: C 53.87, H 3.76, N 23.14%

Smp.: 189-190 °C. M.p.: 189-190 °C.

Eksempel 19 Example 19

3-( 2, 4- dlfluorfenyl)-6-( 2- metyl- 2H- l, 2, 4- triazol- 3- ylmetoksy)-7-( tlen- 2- yl)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 3-(2,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-(thlen-2-yl)-1,2,4-triazolo[ 4, 3-b] pyridazine

Denne forbindelse ble fremstilt som beskrevet i eksempel 18, trinn a), b), c) og d) bortsett fra at 2,4-difluorbenzhydrazid ble anvendt i stedet for 2-fluorbenzhydrazid i trinn c). Tittelforbindelsen ble isolert som et gult, fast materiale (0,01 g). This compound was prepared as described in Example 18, steps a), b), c) and d) except that 2,4-difluorobenzhydrazide was used instead of 2-fluorobenzhydrazide in step c). The title compound was isolated as a yellow solid (0.01 g).

<1>H-NMR (360 MHz, CDC13) 8 3,90 (3 H, s), 5,61 (2 H, s), 7,00-7,16 (3 H, m), 7,50 (1 H, d, J 5 Hz), 7,63 (1 H, d, J 4 Hz), 7,90-7,98 (2 H, m), 8,29 (1 H, s); <1>H-NMR (360 MHz, CDC13) 8 3.90 (3 H, s), 5.61 (2 H, s), 7.00-7.16 (3 H, m), 7.50 (1 H, d, J 5 Hz), 7.63 (1 H, d, J 4 Hz), 7.90-7.98 (2 H, m), 8.29 (1 H, s);

MS (ES<*>) m/e 426 [MH]<*>; MS (ES<*>) m/e 426 [MH]<*>;

Smp.: 209-212 °C. M.p.: 209-212 °C.

Eksempel 20 Example 20

6-( lH- benzimidazol- 2- ylmetoksy)- 7- syklobutyl- 3-( 2, 4- difluor-fenyl)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 6-(1H-benzimidazol-2-ylmethoxy)-7-cyclobutyl-3-(2,4-difluoro-phenyl)-1,2,4-triazolo[4,3-b]pyridazine

a) 7- syklobutyl- 3-( 2, 4- difluorfenyl)- 6-[ l-( 2- trimetyl-silanyletoksymetyl)- lH- benzimidazol- 2- ylmetoksy]-1, 2, 4- triazolo[ 4, 3- b] pyridazin a) 7- cyclobutyl- 3-( 2, 4- difluorophenyl)- 6-[ 1-( 2- trimethyl-silanylethoxymethyl)- 1H- benzimidazol- 2- ylmethoxy]-1, 2, 4- triazolo[ 4, 3- b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyrene beskrevet i eksempel 1, trinn a), b) og c), under anvendelse av 2,4-difluorbenzhydrazid i stedet for 2-fluorbenzhydrazid i trinn b), og ved anvendelse av [l-(2-trimetyl-silanyletoksymetyl)-lH-benzimidazol-2-yl]metanol (fremstilt som beskrevet i J. Org. Chem., 1986, 1891) i stedet for (2-metyl-2H-l,2,4-triazol-3-yl)metanol i trinn c). Data for tittelforbindelsen :<1>H-NMR (250 MHz, CDC13) 8 7,94 (3 H, m), 7,59 (1 H, m), 7,45 (2 H, m), 7,14 (2 H, m), 5,74 (2 H, s), 5,65 (2 H, s), 3,71 (1 H, m), 3,59 (2 H, t), 1,90-2,46 (6 H, m), 0,93 This compound was prepared using the procedures described in Example 1, steps a), b) and c), using 2,4-difluorobenzhydrazide in place of 2-fluorobenzhydrazide in step b), and using [l-( 2-trimethyl-silanylethoxymethyl)-1H-benzimidazol-2-yl]methanol (prepared as described in J. Org. Chem., 1986, 1891) instead of (2-methyl-2H-1,2,4-triazol- 3-yl)methanol in step c). Data for the title compound :<1>H-NMR (250 MHz, CDCl 3 ) δ 7.94 (3 H, m), 7.59 (1 H, m), 7.45 (2 H, m), 7.14 (2 H, m), 5.74 (2 H, s), 5.65 (2 H, s), 3.71 (1 H, m), 3.59 (2 H, t), 1.90 -2.46 (6 H, m), 0.93

(2 H, t), 0,00 (9 H, m); (2 H, h), 0.00 (9 H, m);

MS (ES<*>) m/e 563 [MH]<*>. MS (ES<*>) m/e 563 [MH]<*>.

b) 6-( lH- benzimidazol- 2- ylmetoksy)- 7- syklobutyl- 3-( 2, 4-difluorfenyl)- l, 2, 4- triazolo[ 4, 3- b] pyridazin b) 6-(1H-benzimidazol-2-ylmethoxy)-7-cyclobutyl-3-(2,4-difluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine

En løsning av 7-syklobutyl-3-(2,4-difluorfenyl)-6-[l-(2-trimetylsilanyletoksymetyl)-lH-benzimidazol-2-ylmetoksy]-l,2,4-triazolo[4,3-b]pyridazin (187 mg, 0,333 mmol) i 10 ml 5 M saltsyre og 4 ml etanol ble oppvarmet til 80 °C over natten og ble deretter konsentrert i vakuum for å fjerne løsnings-midlene. Mettet kaliumkarbonatløsning ble tilsatt, hvorpå blandingen ble fortynnet med vann, ble filtrert, og det gjen-værende faste materialet ble vasket med vann og deretter eter og ble tørket. Residuet ble renset ved flashkromatografi på silikagel under anvendelse av etylacetat som elueringsmiddel under dannelse av tittelforbindelsen (60 mg, 42 %). Data for tittelforbindelsen: A solution of 7-cyclobutyl-3-(2,4-difluorophenyl)-6-[1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-ylmethoxy]-1,2,4-triazolo[4,3-b ]pyridazine (187 mg, 0.333 mmol) in 10 mL of 5 M hydrochloric acid and 4 mL of ethanol was heated to 80 °C overnight and then concentrated in vacuo to remove the solvents. Saturated potassium carbonate solution was added, whereupon the mixture was diluted with water, filtered, and the remaining solid washed with water and then ether and dried. The residue was purified by flash chromatography on silica gel using ethyl acetate as eluent to give the title compound (60 mg, 42%). Data for the title compound:

<L>H-NMR (250 MHz, CDC13) 6 10,62 (1 H, br s), 7,85 <L>H-NMR (250 MHz, CDC13) 6 10.62 (1 H, br s), 7.85

(2 H, m), 7,56 (1 H, d, J 1,6 Hz), 7,48 (1 H, br s), 7,32 (2 H, m), 7.56 (1 H, d, J 1.6 Hz), 7.48 (1 H, br s), 7.32

(2 H, m), 7,00 (2 H, m), 5,65 (2 H, s), 3,54 (1 H, m), 2,24 (2 H, m), 7.00 (2 H, m), 5.65 (2 H, s), 3.54 (1 H, m), 2.24

(2 H, m), 2,01 (3 H, m), 1,80 (1 H, rn); (2H, m), 2.01 (3H, m), 1.80 (1H, rn);

MS (ES<+>) m/e 433 [MH]<+>. MS (ES<+>) m/e 433 [MH]<+>.

Eksempel 21 Example 21

3-( 2, 4- difluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol- 3- ylmetoksy)-7-( pyrrolidin- l- yl)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 3-(2,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-(pyrrolidin-1-yl)-1,2,4-triazolo[ 4, 3-b] pyridazine

a) 4- brom- 3, 6- diklorpyridazin a) 4-bromo-3,6-dichloropyridazine

En løsning av 4-brom-l,2-dihydropyridazin-3,6-dion A solution of 4-bromo-1,2-dihydropyridazine-3,6-dione

(eksempel 18, trinn a) (10 g, 52 mmol) i 100 ml fosforoksyklorid ble omrørt og oppvarmet til 100 °C under nitrogen i 16 t. Etter avkjøling ble overskuddet av fosforoksyklorid fjernet i vakuum. Residuet ble behandlet azeotropt 2 ganger med toluen, ble deretter tatt opp i diklormetan/vann. Blandingen ble forsiktig gjort basisk med natriumhydrogenkarbonat (fast). Det var nødvendig å fortynne blandingen ytterligere for å oppnå to klare lag. De to lag ble separert og det vandige lag ble ekstrahert 3 ganger med diklormetan. De kombinerte ekstrakter ble tørket (Na2S04), filtrert og fordampet. Residuet ble renset ved kromatografi på silikagel og eluering med diklormetan under dannelse av tittelpyridazinet (5,0 g, (Example 18, step a) (10 g, 52 mmol) in 100 ml phosphorus oxychloride was stirred and heated to 100 °C under nitrogen for 16 h. After cooling, the excess phosphorus oxychloride was removed in vacuo. The residue was azeotroped twice with toluene, then taken up in dichloromethane/water. The mixture was carefully basified with sodium bicarbonate (solid). It was necessary to dilute the mixture further to achieve two clear layers. The two layers were separated and the aqueous layer was extracted 3 times with dichloromethane. The combined extracts were dried (Na 2 SO 4 ), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with dichloromethane to give the title pyridazine (5.0 g,

42 %) som et fargeløst, fast materiale. 42%) as a colourless, solid material.

^-NMR (250 MHz, CDC13) 7,68 (br s); 3-NMR (250 MHz, CDCl 3 ) 7.68 (br s);

MS (ES<+>) 230 [MH]<+>, 228 [MH]<+>. MS (ES<+>) 230 [MH]<+>, 228 [MH]<+>.

b) 3, 6- diklor- 4-( pyrrolidin- l- yl) pyridazin b) 3,6-dichloro-4-(pyrrolidin-1-yl)pyridazine

Pyrrolidin (3,36 ml, 40 mmol) ble tilsatt til en om-rørt løsning/suspensjon av 4-brom-3,6-diklorpyridazin (8,3 g, 36 mmol) og kaliumkarbonat (13,8 g, 0,1 mol) i 100 ml tørr DMF ved romtemperatur under nitrogen. Blandingen ble omrørt ved romtemperatur i 16 t og deretter ved 60 °C i 3 t. Reaksjonsblandingen ble helt over i 250 ml vann. Det vandige lag ble ekstrahert 3 ganger med etylacetat. De kombinerte ekstrakter ble tørket (MgS0<), ble filtrert og fordampet. Residuet ble renset ved kromatografi på silikagel og eluering med 0,5 % metanol/diklormetan under dannelse av tittelpyridazinet (7,2 g, 92 %) som en fargeløs olje. Pyrrolidine (3.36 mL, 40 mmol) was added to a stirred solution/suspension of 4-bromo-3,6-dichloropyridazine (8.3 g, 36 mmol) and potassium carbonate (13.8 g, 0.1 mol) in 100 ml dry DMF at room temperature under nitrogen. The mixture was stirred at room temperature for 16 h and then at 60 °C for 3 h. The reaction mixture was poured into 250 ml of water. The aqueous layer was extracted 3 times with ethyl acetate. The combined extracts were dried (MgSO 4 ), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 0.5% methanol/dichloromethane to give the title pyridazine (7.2 g, 92%) as a colorless oil.

<1>H-NMR (250 MHz, CDC13) 2,00-2,05 (4 H, m), 3,61-3,69 (4 H, m), 6,46 (1 H, s); <1>H-NMR (250 MHz, CDCl 3 ) 2.00-2.05 (4 H, m), 3.61-3.69 (4 H, m), 6.46 (1 H, s);

MS (ES<+>) 218 [MH]\ 220 [MH]\ MS (ES<+>) 218 [MH]\ 220 [MH]\

c) 3- klor- 6- hydrazino- 4-( pyrrolidin- l- yl) pyridazin 3,6-diklor-4-(pyrrolidin-l-yl)pyridazin (7,2 g, 33 mmol) og hydrazinhydrat (9,96 g, 0,2 mol) ble oppvarmet til tilbakeløpskoking i 130 ml dioksan i 6 t. Etter avkjøling krystalliserte den ønskede isomer fra reaksjonsblandingen og ble oppsamlet ved filtrering (4,1 g, 58 %). c) 3-chloro-6-hydrazino-4-(pyrrolidin-l-yl)pyridazine 3,6-dichloro-4-(pyrrolidin-l-yl)pyridazine (7.2 g, 33 mmol) and hydrazine hydrate (9, 96 g, 0.2 mol) was heated to reflux in 130 mL of dioxane for 6 h. After cooling, the desired isomer crystallized from the reaction mixture and was collected by filtration (4.1 g, 58%).

<1>H-NMR (250 MHz, d6-DMS0) 1,79-1,84 (4 H, m), 3,25-3,40 (4 H, m), 4,12 (2 H, br), 6,09 (1 H, s), 7,47 (1 H, s); <1>H-NMR (250 MHz, d6-DMS0) 1.79-1.84 (4 H, m), 3.25-3.40 (4 H, m), 4.12 (2 H, br ), 6.09 (1H, s), 7.47 (1H, s);

MS (ES<+>) 214 [MH] + , 216 [MH]\ MS (ES<+>) 214 [MH] + , 216 [MH]\

d) N-[ 6- klor- 5-( pyrrolidin- l- yl)- pyridazin- 3- yl]-N' - ( 2, 4- difluorbenzyliden) hydrazin d) N-[6-chloro-5-(pyrrolidin-1-yl)-pyridazin-3-yl]-N'- (2, 4- difluorobenzylidene) hydrazine

3-klor-6-hydrazino-4-(pyrrolidin-l-yl)pyridazin (1,06 g, 4,9 mmol) og 2,4-difluorbenzaldehyd (437 ml, 3-Chloro-6-hydrazino-4-(pyrrolidin-1-yl)pyridazine (1.06 g, 4.9 mmol) and 2,4-difluorobenzaldehyde (437 mL,

4,9 mmol) ble omrørt i 30 ml 0,2 M saltsyre i 2 t. Det utfelte imin ble deretter oppsamlet ved filtrering og ble tørket (1,37 g, 92 %). 4.9 mmol) was stirred in 30 mL of 0.2 M hydrochloric acid for 2 h. The precipitated imine was then collected by filtration and dried (1.37 g, 92%).

MS (ES<*>) 338 [MH]<+>, 340 [MH]\ MS (ES<*>) 338 [MH]<+>, 340 [MH]\

e) 6- klor- 3-( 2, 4- difluorfenyl)- 7-( pyrrolidin- l- yl) - 1, 2, 4- triazolo[ 4f 3- b] pyridazin e) 6-chloro-3-(2,4-difluorophenyl)-7-(pyrrolidin-1-yl)-1,2,4-triazolo[4f 3-b]pyridazine

Jern(III)klorid (4,74 g, 17,5 mmol) i 30 ml etanol ble dråpevis tilsatt til en løsning av det foregående imin (1,06 g, 3,5 mmol) i 60 ml etanol og ble oppvarmet til 60 °C. Etter 6 t ble reaksjonsblandingen fordelt mellom 250 ml diklormetan og 250 ml saltvann. Den organiske fase ble tørket Ferric chloride (4.74 g, 17.5 mmol) in 30 mL of ethanol was added dropwise to a solution of the preceding imine (1.06 g, 3.5 mmol) in 60 mL of ethanol and was heated to 60 °C. After 6 h, the reaction mixture was distributed between 250 ml dichloromethane and 250 ml brine. The organic phase was dried

(MgS04), filtrert og fordampet. Residuet ble renset ved kromatografi på silikagel og eluering med etylacetat-heksanblandinger under dannelse av tittelpyridazinet (0,7 g, 66 %). (MgSO 4 ), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate-hexane mixtures to give the title pyridazine (0.7 g, 66%).

<l>H-NMR (250 MHz, CDC13) 2,02-2,08 (4 H, m), 3,53-3,58 (4 H, m), 6,98-7,09 (2 H, m), 7,46-7,56 (1 H, m), 7,81-7,92 <l>H-NMR (250 MHz, CDCl 3 ) 2.02-2.08 (4 H, m), 3.53-3.58 (4 H, m), 6.98-7.09 (2 H , m), 7.46-7.56 (1 H, m), 7.81-7.92

(1 H, m); (1 H, m);

MS (ES<*>) 336 [MH]<+>, 338 [MH]<+.>MS (ES<*>) 336 [MH]<+>, 338 [MH]<+.>

f) 3-( 2, 4- dlfluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol- 3-ylmetoksy)- 7-( pyrrolidin- l- yl)- l, 2, 4- triazolo[ 4, 3-b] pyridazin f) 3-(2,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-(pyrrolidin-1-yl)-1,2,4- triazolo[4,3-b]pyridazine

Natriumhydrid (60 % dispersjon i olje, 16 mg, Sodium hydride (60% dispersion in oil, 16 mg,

0,41 mmol) ble tilsatt til en løsning av (2-metyl-2H-l,2,4-triazol-3-yl)metanol (fremstilt under anvendelse av betingelsene beskrevet i EP-A-421210) (38 mg, 0,33 mmol) i 2 ml tørr DMF ved romtemperatur. Etter 1 t ved romtemperatur ble en løs-ning av 6-klor-3-(2,4-difluorfenyl)-7-(pyrrolidin-l-yl)-1,2,4-triazolo[4,3-b]pyridazin (102 mg, 0,30 mmol) tilsatt og reaksjonsblandingen ble omrørt i 18 t. Residuet ble fordelt mellom diklormetan og vann. Den vandige fase ble ytterligere ekstrahert med 2 x 100 ml diklormetan. De kombinerte ekstrakter ble tørket (Na2S04), filtrert og fordampet. Residuet ble renset ved kromatografi på silikagel og ble eluert med 0-2 % etylacetat-metanol under dannelse av tittelpyridazinet (42 mg, 30 %). 0.41 mmol) was added to a solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (prepared using the conditions described in EP-A-421210) (38 mg, 0 .33 mmol) in 2 ml of dry DMF at room temperature. After 1 h at room temperature, a solution of 6-chloro-3-(2,4-difluorophenyl)-7-(pyrrolidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine (102 mg, 0.30 mmol) added and the reaction mixture was stirred for 18 h. The residue was partitioned between dichloromethane and water. The aqueous phase was further extracted with 2 x 100 ml of dichloromethane. The combined extracts were dried (Na 2 SO 4 ), filtered and evaporated. The residue was purified by chromatography on silica gel and was eluted with 0-2% ethyl acetate-methanol to give the title pyridazine (42 mg, 30%).

hi-NMR (250 MHz, CDC13) 1,73-1,78 (4 H, m), 3,51-3,55 (4 H, m), 3,93 (3 H, s), 5,40 (2 H, s), 6,65 (1 H, s), 6,95-7,03 (2 H, m), 7,92-7,94 (1 H, m), 8,04 (1 H, s), hi-NMR (250 MHz, CDCl 3 ) 1.73-1.78 (4 H, m), 3.51-3.55 (4 H, m), 3.93 (3 H, s), 5.40 (2 H, s), 6.65 (1 H, s), 6.95-7.03 (2 H, m), 7.92-7.94 (1 H, m), 8.04 (1 H, s),

MS (ES<*>) 413 [MH]<+>. MS (ES<*>) 413 [MH]<+>.

Eksempel 22 Example 22

3- ( 2, 4- di fluorfenyl)- 6-( 1- metyl- 1H- 1, 2, 4- triazol- 3- ylmetoksy)-7-( pyrrolidin- l- yl)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 3-(2,4-difluorophenyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-(pyrrolidin-1-yl)-1,2,4-triazolo [4,3-b]pyridazine

Denne forbindelse ble fremstilt som beskrevet i eksempel 21, trinn f), under anvendelse av (1-metyl-lH-l,2,4-triazol-3-yl)metanol (EP-A-421210) i stedet for (2-metyl-2H-1,2,4-triazol-3-yl)metanol. Data for tittelforbindelsen: 1H-NMR (250 MHz, CDC13) 1,95-2,00 (4 H, m), 3,46-3,52 (4 H, m), 3,86 (3 H, s), 5,47 (2 H, s), 6,70 (1 H, s), 6,95-7,11 (2 H, m), 7,78-7,87 (1 H, m), 7,90 (1 H, s). This compound was prepared as described in Example 21, step f), using (1-methyl-1H-1,2,4-triazol-3-yl)methanol (EP-A-421210) instead of (2- methyl (2H-1,2,4-triazol-3-yl)methanol. Data for the title compound: 1H-NMR (250 MHz, CDCl 3 ) 1.95-2.00 (4 H, m), 3.46-3.52 (4 H, m), 3.86 (3 H, s) , 5.47 (2 H, s), 6.70 (1 H, s), 6.95-7.11 (2 H, m), 7.78-7.87 (1 H, m), 7 .90 (1 H, p).

MS (ES<+>) 413 [MH]\ MS (ES<+>) 413 [MH]\

Eksempel 23 Example 23

3-( 2- fluorfenyl)- 6-( l- metyl- lH- l, 2, 4- triazol- 3- ylmetoksy)- 7-( pyrrolidin- l- yl)- 1, 2, 4- trlazolo[ 4, 3- b] pyridazin 3-(2-fluorophenyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-(pyrrolidin-1-yl)-1,2,4-trazolo[4, 3- b] pyridazine

Fremstilt ved en analog prosedyre som beskrevet i eksempel 21, trinn d), e) og f), under anvendelse av 2-fluor-benzaldehyd i stedet for 2,4-difluorbenzaldehyd i trinn d) og (l-metyl-lH-l,2,4-triazol-3-yl)metanol (EP-A-421210) i stedet for (2-metyl-2H-l,2,4-triazol-3-yl)metanol i trinn f) under dannelse av tittelpyridazinet. Prepared by an analogous procedure as described in Example 21, steps d), e) and f), using 2-fluorobenzaldehyde instead of 2,4-difluorobenzaldehyde in step d) and (l-methyl-lH-l ,2,4-triazol-3-yl)methanol (EP-A-421210) instead of (2-methyl-2H-1,2,4-triazol-3-yl)methanol in step f) to form the title pyridazine .

<1>H-NMR (250 MHz, d6-DMS0) 2,06-2,20 (4 H, m), 3,68-3,74 (4 H, m), 4,00 (3 H, s), 5,72 (2 H, s), 7,07 (1 H, s), 7,60-7,70 (2 H, m), 7,81-7,87 (1 H, m), 8,05-8,11 (1 H, m), 8,17 (1 H, s); <1>H-NMR (250 MHz, d6-DMS0) 2.06-2.20 (4 H, m), 3.68-3.74 (4 H, m), 4.00 (3 H, s ), 5.72 (2 H, s), 7.07 (1 H, s), 7.60-7.70 (2 H, m), 7.81-7.87 (1 H, m), 8.05-8.11 (1H, m), 8.17 (1H, s);

MS (ES<*>) 395 [MH]<+>. MS (ES<*>) 395 [MH]<+>.

Eksempel 24 Example 24

7- syklobutyl- 3-( 2- fluorfenyl)- 6-( 1- metyl- lH- imidazol- 4- yl-metoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 2- fluorophenyl)- 6-( 1- methyl- 1H- imidazol- 4-yl- methoxy)- 1, 2, 4- triazolo[ 4, 3-b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyren beskrevet i eksempel 1, trinn c), med (1-metyl-lH-imidazol-4-yl)metanol i stedet for (2-metyl-2H-l,2,4-triazol-3-y1)metanol. Data for tittelforbindelsen: Smp. = 176 °C; This compound was prepared using the procedure described in Example 1, step c), with (1-methyl-1H-imidazol-4-yl)methanol in place of (2-methyl-2H-1,2,4-triazol- 3-y1)methanol. Data for the title compound: mp. = 176 °C;

<X>H-NMR (360 MHz, CDC13) 8 1,87 (1 H, m), 2,10 (3 H, m), 2,36 (2 H, m), 3,59 (1 H, m), 3,64 (3 H, s), 5,28 (2 H, s), 6,82 (1 H, s), 7,26-7,36 (2 H, m), 7,39 (1 H, s), 7,53 <X>H-NMR (360 MHz, CDCl 3 ) 8 1.87 (1 H, m), 2.10 (3 H, m), 2.36 (2 H, m), 3.59 (1 H, m), 3.64 (3 H, s), 5.28 (2 H, s), 6.82 (1 H, s), 7.26-7.36 (2 H, m), 7.39 (1 H, p), 7.53

(1 H, m), 7,76 (1 H, s), 7,92 (1 H, rn); (1H, m), 7.76 (1H, s), 7.92 (1H, rn);

MS (ES<+>) m/e 379 [MH]<*>. MS (ES<+>) m/e 379 [MH]<*>.

Eksempel 25 Example 25

7-( 1- fluorsyklobutyl)- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4-triazol- 3- ylmetoksy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 7-( 1- fluorocyclobutyl)- 3-( 2- fluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4-triazol- 3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

a) 3- klor- 6- hydrazino- 4-( trimetylsilyl) pyridazin a) 3-chloro-6-hydrazino-4-(trimethylsilyl)pyridazine

Til en løsning av 3,6-diklor-4-(trimetylsilyl)pyridazin (9,67 g, 43,7 mmol) (Turck et al., J. Heterocycl. Chem., 1990, 27, 1377; fremstilt under anvendelse av metoden beskrevet av Trécourt et al-, J. Heterocycl. Chem., 1995, 32, 1057) i en 1,0 M løsning av hydrazin i THF (131 ml, 131 mmol) ble tilsatt N,N-diisopropyletylamin (7,5 ml, 43,8 mmol) og blandingen ble omrørt ved tilbakeløpstemperaturen under nitrogen i 68 t. Blandingen fikk avkjøles, silikagel ble tilsatt og løsnings-midlet ble fordampet i vakuum. Residuet ble deretter renset ved flashkromatografi (silikagel, 5 % MeOH/CH2Cl2) under dannelse av 1,24 g (13 %) av 6-klor-3-hydrazino-4-(trimetylsilyl)-pyridazin og 6,34 g (67 %) av tittelforbindelsen som et gul-brunt, fast materiale; To a solution of 3,6-dichloro-4-(trimethylsilyl)pyridazine (9.67 g, 43.7 mmol) (Turck et al., J. Heterocycl. Chem., 1990, 27, 1377; prepared using the method described by Trécourt et al-, J. Heterocycl. Chem., 1995, 32, 1057) to a 1.0 M solution of hydrazine in THF (131 ml, 131 mmol) was added N,N-diisopropylethylamine (7.5 ml, 43.8 mmol) and the mixture was stirred at the reflux temperature under nitrogen for 68 h. The mixture was allowed to cool, silica gel was added and the solvent was evaporated in vacuo. The residue was then purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) to give 1.24 g (13%) of 6-chloro-3-hydrazino-4-(trimethylsilyl)-pyridazine and 6.34 g (67%) ) of the title compound as a yellow-brown solid;

<X>H-NMR (360 MHz, CDC13) 8 0,39 (9 H, s), 3,96 (2 H, br s), 6,24 (1 H, br s), 7,08 (1 H, s). <X>H-NMR (360 MHz, CDC13) 8 0.39 (9 H, s), 3.96 (2 H, br s), 6.24 (1 H, br s), 7.08 (1 H, pp).

b) 3- klor- 6-[ 2-( 2- fluorbenzoyl) hydrazino]- 4-( trimetylsilyl ) pyridazin b) 3-chloro-6-[2-(2-fluorobenzoyl)hydrazino]-4-(trimethylsilyl)pyridazine

Til en omrørt blanding av 3-klor-6-hydrazino-4-(trimetylsilyl )pyridazin (6,34 g, 29,3 mmol) og vannfri trietylamin (4,9 ml, 35,2 mmol) i 100 ml vannfri dietyleter avkjølt under nitrogen til -4 °C, ble det dråpevis tilsatt i løpet av 13 min, 2-fluorbenzoylklorid (3,5 ml, 29,4 mmol), idet temperaturen ble holdt under 5 °C. Den tykke blanding ble deretter omrørt i 30 min ved 0-5 °C og ble deretter tilsatt 1 ml vannfri metanol. Blandingen ble fortynnet med 100 ml heksan og ble filtrert. Det oppsamlede, faste materialet ble vasket med 2 x 25 ml dietyleter, deretter 100 ml vann, ble deretter oppløst i 300 ml diklormetan og 20 ml metanol, ble vasket med 100 ml mettet, vandig NaCl, ble tørket (Na2S04) og fordampet i vakuum under dannelse av 9,72 g (98 %) av tittelforbindelsen som et blekt brunt, fast materiale; To a stirred mixture of 3-chloro-6-hydrazino-4-(trimethylsilyl)pyridazine (6.34 g, 29.3 mmol) and anhydrous triethylamine (4.9 mL, 35.2 mmol) in 100 mL of anhydrous diethyl ether cooled under nitrogen to -4 °C, 2-fluorobenzoyl chloride (3.5 ml, 29.4 mmol) was added dropwise over 13 min, keeping the temperature below 5 °C. The thick mixture was then stirred for 30 min at 0-5 °C and then 1 ml of anhydrous methanol was added. The mixture was diluted with 100 ml of hexane and was filtered. The collected solid was washed with 2 x 25 mL diethyl ether, then 100 mL water, then dissolved in 300 mL dichloromethane and 20 mL methanol, washed with 100 mL saturated aqueous NaCl, dried (Na 2 SO 4 ) and evaporated in vacuo to give 9.72 g (98%) of the title compound as a pale brown solid;

<1>H-NMR (360 MHz, CDC13) 8 0,36 (9 H, s), 7,07 (1 H, s), 7,20 (1 H, dd, J = 11,7 og 8,2 Hz), 7,30 (1 H, t, J = <1>H-NMR (360 MHz, CDCl 3 ) δ 0.36 (9 H, s), 7.07 (1 H, s), 7.20 (1 H, dd, J = 11.7 and 8, 2 Hz), 7.30 (1 H, t, J =

7.6 Hz), 7,55 (1 H, m), 8,00 (1 H, br s), 8,07 (1 H, td, J = 7.7 og 1,8 Hz), 9,19 (1 H, br s); 7.6 Hz), 7.55 (1 H, m), 8.00 (1 H, br s), 8.07 (1 H, td, J = 7.7 and 1.8 Hz), 9.19 (1 H , br s);

MS (ES<+>) m/e 339/341 [MH]<+>, 217/219 [M-COC6H4F+2H]\ c) 6- klor- 3-( 2- fluorfenyl)- 7-( trimetylsilyl)- l, 2, 4- triazolo[ 4, 3- b] pyridazin MS (ES<+>) m/e 339/341 [MH]<+>, 217/219 [M-COC6H4F+2H]\ c) 6-chloro-3-(2-fluorophenyl)-7-(trimethylsilyl) - 1,2,4-triazolo[4,3-b]pyridazine

Til en omrørt suspensjon av 3-klor-6-[2-(2-fluorbenzoyl )hydrazino] -4- (trimetylsilyl )pyridazin (9,72 g, 28,7 mmol) og 1,2-dibromtetrakloretan (18,68 g, 57,4 mmol) i 170 ml vann fri acetonitril, avkjølt under nitrogen til 1 °C, ble det por-sjonsvis tilsatt i løpet av 21 min fast trifenylfosfin (30,10 g, 115 mmol), idet temperaturen ble holdt under 5 °C. Blandingen ble omrørt ved 2 °C i 10 min, hvoretter vannfri trietylamin (32,0 ml, 230 mmol) ble dråpevis tilsatt i løpet av 18 min idet temperaturen ble holdt under 6 °C. Blandingen ble deretter omrørt ved 0-3 °C under nitrogen i 85 min. Blandingen ble deretter fortynnet med 150 ml diklormetan og ble vasket med 200 ml vann. Det organiske lag ble tørket (Na2S04) og fordampet i vakuum. Residuet ble renset ved flashkromatografi (silikagel, 20-40 % EtOAc/heksan) under dannelse av 7,67 g (83 %) av tittelforbindelsen som et hvitt, fast materiale; To a stirred suspension of 3-chloro-6-[2-(2-fluorobenzoyl)hydrazino]-4-(trimethylsilyl)pyridazine (9.72 g, 28.7 mmol) and 1,2-dibromotetrachloroethane (18.68 g , 57.4 mmol) in 170 ml of water-free acetonitrile, cooled under nitrogen to 1 °C, solid triphenylphosphine (30.10 g, 115 mmol) was added portionwise over 21 min, keeping the temperature below 5 °C. The mixture was stirred at 2 °C for 10 min, after which anhydrous triethylamine (32.0 mL, 230 mmol) was added dropwise over 18 min while maintaining the temperature below 6 °C. The mixture was then stirred at 0-3 °C under nitrogen for 85 min. The mixture was then diluted with 150 ml of dichloromethane and was washed with 200 ml of water. The organic layer was dried (Na 2 SO 4 ) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 20-40% EtOAc/hexane) to give 7.67 g (83%) of the title compound as a white solid;

^-NMR (360 MHz, CDC13) 8 0,48 (9 H, s), 7,30 (1 H, dd, J = 10,1 og 8,8 Hz), 7,36 (1 H, td, J = 7,6 og 1,1 Hz), 7,58 (1 H, m), 7,90 (1 H, td, J = 7,3 og 1,8 Hz), 8,30 (1 H, s); ^-NMR (360 MHz, CDCl 3 ) δ 0.48 (9 H, s), 7.30 (1 H, dd, J = 10.1 and 8.8 Hz), 7.36 (1 H, td, J = 7.6 and 1.1 Hz), 7.58 (1 H, m), 7.90 (1 H, td, J = 7.3 and 1.8 Hz), 8.30 (1 H, s);

MS (ES<+>) m/e 321/323 [MH]<+>. MS (ES<+>) m/e 321/323 [MH]<+>.

d) 6- klor- 3-( 2- fluorfenyl)- 7-( 1- hydroksysyklobutyl )-1, 2, 4- triazolo[ 4, 3- b] pyridazin d) 6-chloro-3-(2-fluorophenyl)-7-(1-hydroxycyclobutyl)-1,2,4-triazolo[4,3-b]pyridazine

Til en omrørt løsning av 6-klor-3-(2-fluorfenyl)-7-(trimetylsilyl)-l,2,4-triazolo[4,3-b]pyridazin (1,04 g, To a stirred solution of 6-chloro-3-(2-fluorophenyl)-7-(trimethylsilyl)-1,2,4-triazolo[4,3-b]pyridazine (1.04 g,

3,24 mmol) i 15 ml vannfriTHF under nitrogen ble det tilsatt syklobutanon (1,21 ml, 16,2 mmol), etterfulgt av fast tetrabutylammoniumdifluortrifenylstannat (0,410 g, 0,650 mmol). Kolben ble fordampet og fylt på nytt med nitrogen fire ganger, ble deretter omrørt ved romtemperatur i 5,75 t. Ytterligere tetrabutylammoniumdifluortrifenylstannat (0,403 g, 0,639 mmol) ble tilsatt og blandingen ble omrørt i ytterligere 36 t. Blandingen ble deretter fordelt mellom 75 ml diklormetan og 3.24 mmol) in 15 mL of anhydrous THF under nitrogen was added cyclobutanone (1.21 mL, 16.2 mmol), followed by solid tetrabutylammonium difluorotriphenylstannate (0.410 g, 0.650 mmol). The flask was evaporated and refilled with nitrogen four times, then stirred at room temperature for 5.75 h. Additional tetrabutylammonium difluorotriphenylstannate (0.403 g, 0.639 mmol) was added and the mixture was stirred for an additional 36 h. The mixture was then partitioned between 75 mL dichloromethane and

75 ml vann. Det vandige lag ble ekstrahert ytterligere med 75 ml of water. The aqueous layer was further extracted with

2 x 50 ml diklormetan, og de kombinerte, organiske ekstrakter ble tørket (Na2S04) og fordampet i vakuum. Residuet ble renset ved flashkromatograf! (silikagel, 70-100 % EtOAc/heksan) under dannelse av 0,2634 g (26 %) av tittelforbindelsen som et krem-farget, fast materiale; 2 x 50 mL dichloromethane, and the combined organic extracts were dried (Na 2 SO 4 ) and evaporated in vacuo. The residue was purified by flash chromatography! (silica gel, 70-100% EtOAc/hexane) to give 0.2634 g (26%) of the title compound as a cream-colored solid;

hi-NMR (360 MHz, CDC13) 8 1,81 (1 H, m), 2,27 (1 H, m), 2,52 (2 H, m), 2,72 (2 H, m), 2,87 (1 H, s), 7,30 (1 H, t, hi-NMR (360 MHz, CDCl 3 ) δ 1.81 (1 H, m), 2.27 (1 H, m), 2.52 (2 H, m), 2.72 (2 H, m), 2.87 (1 H, s), 7.30 (1 H, t,

J = 9,3 Hz), 7,36 (1 H, t, J=7,5 Hz), 7,58 (1 H, m), 7,88 J = 9.3 Hz), 7.36 (1 H, t, J=7.5 Hz), 7.58 (1 H, m), 7.88

(1 H, td, J - 7,3 og 1,8 Hz), 8,12 (1 H, s); (1 H, td, J - 7.3 and 1.8 Hz), 8.12 (1 H, s);

MS (ES<*>) m/ e 319/321 [MH]<*>, 249. MS (ES<*>) w/ e 319/321 [MH]<*>, 249.

e) 7-( 1- fluorsyklobutyl)- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H-1, 2, 4- triazol- 3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyrl-dazln e) 7-( 1- fluorocyclobutyl)- 3-( 2- fluorophenyl)- 6-( 2- methyl- 2H-1, 2, 4- triazol- 3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyrl-dazln

Til en omrørt løsning av (2-metyl-2H-l,2,4-triazol-3-yl)metanol (0,2206 g, 1,95 mmol) i 6 ml vannfri DMF under nitrogen, ble det tilsatt natriumhydrid (60 % dispersjon i olje, 77,7 mg, 1,94 mmol) og blandingen ble omrørt ved romtemperatur i 20 min. Blandingen ble deretter avkjølt i et is-vannbad og en løsning av 6-klor-3-(2-fluorfenyl)-7-(1-hydroksysyklobutyl)-l,2,4-triazolo[4,3-b]pyridazin (0,2573 g, 0,807 mmol) i 5 ml vannfri DMF ble dråpevis tilsatt i løpet av 5 min. Blandingen ble omrørt i 20 min under nitrogen, ble deretter helt over i 50 ml vandig NH4C1, 25 ml mettet vandig NaCl og 75 ml diklormetan. Det vandige lag ble ytterligere ekstrahert med 2 x 50 ml diklormetan og de kombinerte, organiske ekstrakter ble tørket (Na2S04) og fordampet i vakuum. Residuet ble renset ved flashkromatografi (silikagel, 3-5 % MeOH/CH2Cl2) under dannelse av 0,2793 g 3-(2-fluorfenyl)-7-(1-hydroksysyklobutyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin (inneholdende tilnærmet 20 % (2-metyl-2H-l,2,4-triazol-3-yl)metanol-utgangsmateriale) som et fargeløst, fast materiale; To a stirred solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.2206 g, 1.95 mmol) in 6 mL of anhydrous DMF under nitrogen was added sodium hydride (60 % dispersion in oil, 77.7 mg, 1.94 mmol) and the mixture was stirred at room temperature for 20 min. The mixture was then cooled in an ice-water bath and a solution of 6-chloro-3-(2-fluorophenyl)-7-(1-hydroxycyclobutyl)-1,2,4-triazolo[4,3-b]pyridazine (0 .2573 g, 0.807 mmol) in 5 ml anhydrous DMF was added dropwise over 5 min. The mixture was stirred for 20 min under nitrogen, then poured into 50 mL aqueous NH 4 Cl, 25 mL saturated aqueous NaCl and 75 mL dichloromethane. The aqueous layer was further extracted with 2 x 50 ml dichloromethane and the combined organic extracts were dried (Na 2 SO 4 ) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 3-5% MeOH/CH2Cl2) to give 0.2793 g of 3-(2-fluorophenyl)-7-(1-hydroxycyclobutyl)-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (containing approximately 20% (2-methyl-2H-1,2,4-triazol-3-yl) methanol starting material) as a colorless solid;

<X>HNMR (360 MHz, CDC13) 8 1,74 (1 H, m), 2,17 (1 H, m), 2,43 (2 H, m), 2,60 (2 H, m), 3,82 (3 H, s), 5,58 (2 H, <X>HNMR (360 MHz, CDC13) 8 1.74 (1 H, m), 2.17 (1 H, m), 2.43 (2 H, m), 2.60 (2 H, m) , 3.82 (3 H, s), 5.58 (2 H,

s), 7,27 (1 H, t, J = 9,6 Hz), 7,36 (1 H, t, J = 7,5 Hz), 7,58 (1 H, m), 7,82 (1 H, m), 7,85 (1 H, s), 8,01 (1 H, s); s), 7.27 (1 H, t, J = 9.6 Hz), 7.36 (1 H, t, J = 7.5 Hz), 7.58 (1 H, m), 7.82 (1 H, m), 7.85 (1 H, s), 8.01 (1 H, s);

MS (ES<*>) m/e 396 [MH]<*>, 114. MS (ES<*>) m/e 396 [MH]<*>, 114.

Til en omrørt løsning av det ovenfor angitte materialet (0,2094 g) i 10 ml vannfri diklormetan, avkjølt til -78 °C under nitrogen, ble det tilsatt dietylaminosvoveltrifluorid (DAST) (77,0 ml, 0,582 mmol) dråpevis, og blandingen ble om-rørt ved mindre enn -70 °C. Ytterligere DAST (2 x 77,0 ml, 0,582 mmol og 40 ml, 0,303 mmol) ble dråpevis tilsatt etter 40, 70 og 110 min. Blandingen ble omrørt ved <-70 °C i ytterligere 40 min, ble deretter fordelt mellom 20 ml mettet, van dig NaHC03og 40 ml diklormetan. Det vandige lag ble ekstrahert med ytterligere 2 x 30 ml diklormetan og de kombinerte organiske ekstrakter ble tørket (Na2S04) og fordampet i vakuum. Residuet ble renset ved flashkromatografi (silikagel, 2 % MeOH/CH2Cl2) under dannelse av 0,1249 g (52 %) av tittelforbindelsen som et hvitt, fast materiale; To a stirred solution of the above material (0.2094 g) in 10 mL anhydrous dichloromethane, cooled to -78 °C under nitrogen, was added diethylaminosulfur trifluoride (DAST) (77.0 mL, 0.582 mmol) dropwise, and the mixture was stirred at less than -70 °C. Additional DAST (2 x 77.0 mL, 0.582 mmol and 40 mL, 0.303 mmol) was added dropwise after 40, 70, and 110 min. The mixture was stirred at <-70 °C for an additional 40 min, then partitioned between 20 mL of saturated aqueous NaHCO 3 and 40 mL of dichloromethane. The aqueous layer was extracted with an additional 2 x 30 mL of dichloromethane and the combined organic extracts were dried (Na 2 SO 4 ) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 2% MeOH/CH 2 Cl 2 ) to give 0.1249 g (52%) of the title compound as a white solid;

Smp.: 154-162 °C (CH2Cl2-Et0Ac-heksan); M.p.: 154-162 °C (CH2Cl2-Et0Ac-hexane);

<l>H NMR (400 MHz, DMS0-d6) 5 1,60 (1 H, m), 1,96 (1 H, m), 2,51 (2 H, m), 2,86 (2 H, m), 3,78 (3 H, s), 5,55 (2 H, <1>H NMR (400 MHz, DMS0-d6) δ 1.60 (1 H, m), 1.96 (1 H, m), 2.51 (2 H, m), 2.86 (2 H , m), 3.78 (3 H, s), 5.55 (2 H,

s), 7,46 (1 H, t, J= 7,8 Hz), 7,50 (1 H, t, J= 9,8 Hz), 7,70 (1 H, m), 7,93 (1 H, m), 7,94 (1 H, s), 8,59 (1 H, d, J = s), 7.46 (1 H, t, J= 7.8 Hz), 7.50 (1 H, t, J= 9.8 Hz), 7.70 (1 H, m), 7.93 (1 H, m), 7.94 (1 H, s), 8.59 (1 H, d, J =

3,0 Hz); 3.0Hz);

MS (ES<+>) m/e 398 [MH]<+>, 378 [M-HF+H] + ; MS (ES<+>) m/e 398 [MH]<+>, 378 [M-HF+H] + ;

Analyse funnet: C 57,61, H 4,18, N 24,47 % Analysis found: C 57.61, H 4.18, N 24.47%

Ci9H17F2N70 kreves: C 57,43, H 4,31, N 24,67 %. C 19 H 17 F 2 N 7 O required: C 57.43, H 4.31, N 24.67%.

Eksempel 26 Example 26

7- syklobutyl- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H- pyrazol- 3- yl-metoksy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclobutyl- 3-( 2- fluorophenyl)- 6-( 2- methyl- 2H- pyrazol- 3- yl- methoxy)- 1, 2, 4- triazolo[ 4, 3-b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyren beskrevet i eksempel 1, trinn c), med (2-metyl-2H-pyrazol-3-yl)metanol (fremstilt under anvendelse av betingelsene beskrevet i EP-A-91130) i stedet for (2-metyl-2H-l,2,4-triazol-3-yl)metanol. Data for tittelforbindelsen: Smp.: 184-186 °C; This compound was prepared using the procedure described in Example 1, step c), with (2-methyl-2H-pyrazol-3-yl)methanol (prepared using the conditions described in EP-A-91130) in place of ( 2-methyl-2H-1,2,4-triazol-3-yl)methanol. Data for the title compound: mp: 184-186 °C;

<X>H NMR (360 MHz, DMSO) 8 1,80 (1 H, m), 1,99 (1 H, m), 2,21 (4 H, m), 3,57 (1 H, m), 3,80 (3 H, s), 5,39 (2 H, <X>H NMR (360 MHz, DMSO) δ 1.80 (1 H, m), 1.99 (1 H, m), 2.21 (4 H, m), 3.57 (1 H, m ), 3.80 (3 H, s), 5.39 (2 H,

s), 6,29 (1 H, s), 7,37 (1 H, s), 7,48 (2 H, m), 7,64 (1 H, m), 7,96 (1 H, m), 8,18 (1 H, s); s), 6.29 (1 H, s), 7.37 (1 H, s), 7.48 (2 H, m), 7.64 (1 H, m), 7.96 (1 H, m), 8.18 (1H, s);

MS (ES<+>) m/e 379 [MH]<+>'MS (ES<+>) m/e 379 [MH]<+>'

Eksempel 27 Example 27

7-( 2, 2- dimetylpropyl)- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H- 1, 2, 4-triazol- 3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- blpyridazin 7-( 2, 2- dimethylpropyl)- 3-( 2- fluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4-triazol- 3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- blpyridazine

a) 7- brom- 6- klor- 3-( 2- fluorfenyl)- 1, 2, 4- triazolo[ 4, 3-b] pyridazin a) 7-bromo-6-chloro-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine

Tetrabutylammoniumdifluortrifenylstannat (6,8 g, 10,8 mmol) ble tilsatt til en suspensjon av 6-klor-3-(2-fluorfenyl)-7-(trimetylsilyl)-l,2,4-triazolo[4,3-blpyridazin Tetrabutylammonium difluorotriphenylstannate (6.8 g, 10.8 mmol) was added to a suspension of 6-chloro-3-(2-fluorophenyl)-7-(trimethylsilyl)-1,2,4-triazolo[4,3-blpyridazine

(3,17 g, 9,88 mmol) fremstilt som beskrevet i eksempel 25, trinn c), og 1,2-dibromtetrafluoretan (6,0 ml, 50 mmol) i 75 ml vannfri THF, og blandingen ble omrørt ved romtemperatur under nitrogen i 18 t. Blandingen ble fortynnet med 100 ml diklormetan, ble filtrert, og filtratet ble konsentrert. Flashkromatografi på silikagel og eluering med 50-100 % EtOAcheksan, ga 7-brom-6-klor-3-(2-fluorfenyl)-l,2,4-triazolo[4,3-b]pyridazin (2,84 g, 88 %) som et off-hvitt, fast materiale; (3.17 g, 9.88 mmol) prepared as described in Example 25, step c), and 1,2-dibromotetrafluoroethane (6.0 mL, 50 mmol) in 75 mL of anhydrous THF, and the mixture was stirred at room temperature under nitrogen for 18 h. The mixture was diluted with 100 mL of dichloromethane, filtered, and the filtrate was concentrated. Flash chromatography on silica gel eluting with 50-100% EtOAchexane gave 7-bromo-6-chloro-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (2.84 g, 88%) as an off-white solid;

<*>H NMR (360 MHz, CDC13) 5 7,31 (1 H, dd, J = 10 og 10 Hz), 7,36 (1 H, ddd, J = 8,8 og 1 Hz), 7,57-7,63 (1 H, m), 7,87 (1 H, ddd, J = 7,7 and 2 Hz), 8,49 (1 H, s); <*>H NMR (360 MHz, CDCl 3 ) δ 7.31 (1 H, dd, J = 10 and 10 Hz), 7.36 (1 H, ddd, J = 8.8 and 1 Hz), 7, 57-7.63 (1 H, m), 7.87 (1 H, ddd, J = 7.7 and 2 Hz), 8.49 (1 H, s);

MS (ES<*>) m/e 327/329/331 [MH]<*>. MS (ES<*>) m/e 327/329/331 [MH]<*>.

b) 7- brom- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol-3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin b) 7-bromo-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b] pyridazine

En løsning av kalium-bis(trimetylsilyl)amid i toluen (16,8 ml, 0,5 M, 8,4 mmol) ble tilsatt til en omrørt løsning av (2-metyl-2H-l,2,4-triazol-3-yl)metanol (0,95 g, 8,4 mmol) i 30 ml vannfri THF ved romtemperatur under nitrogen. Etter 20 min ble suspensjonen avkjølt til 0 °C og en suspensjon av 7-brom-6-klor-3-(2-fluorfenyl)-1,2,4-triazolo[4,3-b]pyridazin (2,28 g, 6,96 mmol) i 100 ml vannfri THF ble dråpevis tilsatt. Blandingen ble omrørt i 3 t ved 0 °C og ble deretter helt over 1 400 ml isvann, ble fortynnet med 100 ml mettet vandig ammo-niumklorid og ble ekstrahert med 3 x 100 ml 9:1 diklormetan-metanol. Ekstraktene ble tørket (Na2S04), ble filtrert og konsentrert. Flashkolonnekromatografi på silikagel og eluering med 3 % metanol-diklormetan ga 7-brom-3-(2-fluorfenyl)-6-(2-metyl-2H-l-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]-pyridazin (1,45 g, 52 %) som et gult, fast materiale; A solution of potassium bis(trimethylsilyl)amide in toluene (16.8 mL, 0.5 M, 8.4 mmol) was added to a stirred solution of (2-methyl-2H-1,2,4-triazol- 3-yl)methanol (0.95 g, 8.4 mmol) in 30 mL anhydrous THF at room temperature under nitrogen. After 20 min, the suspension was cooled to 0 °C and a suspension of 7-bromo-6-chloro-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (2.28 g , 6.96 mmol) in 100 ml anhydrous THF was added dropwise. The mixture was stirred for 3 h at 0 °C and then poured into 1400 ml of ice water, diluted with 100 ml of saturated aqueous ammonium chloride and extracted with 3 x 100 ml of 9:1 dichloromethane-methanol. The extracts were dried (Na 2 SO 4 ), filtered and concentrated. Flash column chromatography on silica gel and eluting with 3% methanol-dichloromethane gave 7-bromo-3-(2-fluorophenyl)-6-(2-methyl-2H-1-1,2,4-triazol-3-ylmethoxy)-1,2, 4-Triazolo[4,3-b]-pyridazine (1.45 g, 52%) as a yellow solid;

<X>H NMR (360 MHz, CDC13) 5 3,95 (3 H, s), 5,54 (2 H, s), 7,28 (1 H, dd, J = 10 og 10 Hz), 7,37 (1 H, ddd, J = <X>H NMR (360 MHz, CDCl 3 ) δ 3.95 (3 H, s), 5.54 (2 H, s), 7.28 (1 H, dd, J = 10 and 10 Hz), 7 .37 (1 H, ddd, J =

8,8 og 1 Hz), 7,57-7,63 (1 H, m), 7,86 (1 H, ddd, J = 8,8 og 2 Hz), 7,90 (1 H, s), 8,41 (1 H, s); 8.8 and 1 Hz), 7.57-7.63 (1 H, m), 7.86 (1 H, ddd, J = 8.8 and 2 Hz), 7.90 (1 H, s) , 8.41 (1H, s);

MS (ES<*>) m/e 404/406 [MH]<+>. MS (ES<*>) m/e 404/406 [MH]<+>.

C) 7-( 2, 2- dlmetylpropyl)- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H-1, 2, 4- triazol- 3- ylmetoksy)- 1, 2, 4- trlazolo[ 4, 3-b] pyridazin C) 7-(2,2-dlmethylpropyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-trazolo[ 4, 3-b] pyridazine

1,2-dibrometan (0,03 ml, 10 mol %) ble tilsatt til en omrørt suspensjon av syrevasket sinkstøv (0,45 g, 7,0 mmol) i 3 ml vannfri DMF ved 50 °C under nitrogen. Etter 5 min ble neopentyljodid (1,0 ml, 7,5 mmol) tilsatt. Blandingen ble omrørt i 2,5 t under dannelse av en grågrønn, melkeaktig løsning. En blanding av 7-brom-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin (0,35 g, 1,2-Dibromoethane (0.03 mL, 10 mol %) was added to a stirred suspension of acid-washed zinc dust (0.45 g, 7.0 mmol) in 3 mL of anhydrous DMF at 50 °C under nitrogen. After 5 min, neopentyl iodide (1.0 mL, 7.5 mmol) was added. The mixture was stirred for 2.5 h to form a grey-green, milky solution. A mixture of 7-bromo-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b ]pyridazine (0.35 g,

0,866 mmol), tri-2-furylfosfin (0,08 g, 40 mol %) og tris(di-benzylidenaceton)dipalladium(O) (0,04 g, 5 mol%) i 2 ml vannfri DMF ble omrørt ved 50 °C under nitrogen i 15 min, etterfulgt av tilsetning av løsningen av organosinkreagenset via sprøyte. Etter 2,5 t ble blandingen avkjølt, ble helt over i 100 ml vann og ekstrahert med 2 x 50 ml diklormetan. Ekstraktene ble tørket (Na2S04), ble filtrert og konsentrert. Flashkolonnekromatografi på silikagel og eluering med 2 % metanol-diklormetan ga et brunt, fast materiale som ble omkrystallisert fra etylacetat-dietyleter under dannelse av 7-(2,2-di-metylpropyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-blpyridazin (0,199 g, 58 %) som et beigefarget pulver; 0.866 mmol), tri-2-furylphosphine (0.08 g, 40 mol%) and tris(di-benzylideneacetone)dipalladium(O) (0.04 g, 5 mol%) in 2 mL anhydrous DMF was stirred at 50 ° C under nitrogen for 15 min, followed by addition of the solution of the organozinc reagent via syringe. After 2.5 h, the mixture was cooled, poured into 100 ml of water and extracted with 2 x 50 ml of dichloromethane. The extracts were dried (Na 2 SO 4 ), filtered and concentrated. Flash column chromatography on silica gel eluting with 2% methanol-dichloromethane gave a brown solid which was recrystallized from ethyl acetate-diethyl ether to give 7-(2,2-dimethylpropyl)-3-(2-fluorophenyl)-6-( 2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-blpyridazine (0.199 g, 58%) as a beige powder;

<X>H NMR (360 MHz, CDC13) 8 0,96 (9 H, s), 2,61 (2 H, s), 3,83 (3 H, s), 5,47 (2 H, s), 7,28 (1 H, dd, J = 10 og 10 Hz), 7,36 (1 H, dd, J = 8 og 8 Hz), 7,56-7,62 (1 H, m), 7,83 (1 H, s), 7,86 (1 H, dd, J = 8 og 8 Hz), 7,90 (1 H, s); <X>H NMR (360 MHz, CDCl 3 ) δ 0.96 (9 H, s), 2.61 (2 H, s), 3.83 (3 H, s), 5.47 (2 H, s ), 7.28 (1 H, dd, J = 10 and 10 Hz), 7.36 (1 H, dd, J = 8 and 8 Hz), 7.56-7.62 (1 H, m), 7.83 (1 H, s), 7.86 (1 H, dd, J = 8 and 8 Hz), 7.90 (1 H, s);

MS (ES<+>) m/e 396 [MH]<+>; MS (ES<+>) m/e 396 [MH]<+>;

Analyse funnet: C 59,66, H 5,69, N 24,41 % C20H22FN7O-0,4 H20 kreves: C 59,66, H 5,71, N 24,35 %. Analysis found: C 59.66, H 5.69, N 24.41% C 20 H 22 FN 7 O-0.4 H 2 O required: C 59.66, H 5.71, N 24.35 %.

Eksempel 28 Example 28

3-( 2- fluorfenyl)- 7-( 2- metylpropyl)- 6-( 2- metyI- 2H- l, 2, 4- triazol- 3- ylmetoksy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 3-( 2- fluorophenyl)- 7-( 2- methylpropyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol- 3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyren beskrevet i eksempel 27, trinn c), med l-jod-2-metylpropan anvendt i stedet for neopentyljodid. Data for tittelforbindelsen: Smp.: 134-136 °C (EtOAc); This compound was prepared using the procedure described in Example 27, step c), with 1-iodo-2-methylpropane used in place of neopentyl iodide. Data for the title compound: mp: 134-136 °C (EtOAc);

<X>H NMR (360 MHz, CDC13) 8 0,97 (6 H, d, J = 7 Hz), 1,92-2,60 (1 H, m), 2,54 (2 H, d, J = 7 Hz), 3,84 (3 H, s), 5,49 (2 H, s), 7,25-7,30 (1 H, m), 7,36 (1 H, dd, J = 8 og 8 Hz), 7,56-7,62 (1 H, m), 7,83 (1 H, s), 7,83-7,87 (1 H, m), 7,89 (1 H, s); <X>H NMR (360 MHz, CDCl 3 ) δ 0.97 (6 H, d, J = 7 Hz), 1.92-2.60 (1 H, m), 2.54 (2 H, d, J = 7 Hz), 3.84 (3 H, s), 5.49 (2 H, s), 7.25-7.30 (1 H, m), 7.36 (1 H, dd, J = 8 and 8 Hz), 7.56-7.62 (1 H, m), 7.83 (1 H, s), 7.83-7.87 (1 H, m), 7.89 (1 H, s);

MS (ES<*>) m/e 382 [MH]<*>; MS (ES<*>) m/e 382 [MH]<*>;

Analyse funnet: C 59,66, H 5,39, N 25,56 % Analysis found: C 59.66, H 5.39, N 25.56%

C19H20FN,0 kreves: C 59,83, H 5,29, N 24,71 %. C19H20FN,0 required: C 59.83, H 5.29, N 24.71%.

Eksempel 29 Example 29

3-( 2- fluorfenyl)- 7-( 3- metylbutyl)- 6- ( 2- metyl- 2H- l, 2, 4- triazol-3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 3-( 2- fluorophenyl)- 7-( 3- methylbutyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol-3-ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyren beskrevet i eksempel 27, trinn c), med l-jod-3-metylbutan anvendt i stedet for neopentyljodid. Data for tittelforbindelsen: Smp.: 103-105 °C (EtOAc); This compound was prepared using the procedure described in Example 27, step c), with 1-iodo-3-methylbutane used instead of neopentyl iodide. Data for the title compound: mp: 103-105 °C (EtOAc);

<X>H NMR (360 MHz, CDC13) 8 0,95 (6 H, d, J - 6 Hz), 1,15-1,57 (2 H, m), 1,61-1,70 (1 H, m), 2,66 (2 H, dd, J = 8 og 8 Hz), 3,85 (3 H, s), 5,50 (2 H, s) 7,24-7,30 (1 H, m), 7,35 (1 H, dd, J = 7 og 7 Hz), 7,52-7,60 (1 H, m), 7,82-7,86 <X>H NMR (360 MHz, CDCl 3 ) δ 0.95 (6 H, d, J - 6 Hz), 1.15-1.57 (2 H, m), 1.61-1.70 (1 H, m), 2.66 (2 H, dd, J = 8 and 8 Hz), 3.85 (3 H, s), 5.50 (2 H, s) 7.24-7.30 (1 H, m), 7.35 (1 H, dd, J = 7 and 7 Hz), 7.52-7.60 (1 H, m), 7.82-7.86

(1 H, m), 7,85 (1 H, s), 7,89 (1 H, s); (1H, m), 7.85 (1H, s), 7.89 (1H, s);

MS (ES<*>) m/e 396 [MH]<*>; MS (ES<*>) m/e 396 [MH]<*>;

Analyse funnet: C 60,56, H 5,61 % Analysis found: C 60.56, H 5.61%

C20H22FN7O kreves: C 60,75, H 5,61 %. C20H22FN7O required: C 60.75, H 5.61%.

Eksempel 30 Example 30

7- syklopentylmetyl- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol- 3- ylmetoksy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 7- cyclopentylmethyl- 3-( 2- fluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol- 3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

a) 3-( 2- fluorfenyl)-7-jod-6-( 2- metyl- 2H- l, 2, 4- triazol- 3-ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin a) 3-(2-fluorophenyl)-7-iodo-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b] pyridazine

En løsning av 6-klor-3-(2-fluorfenyl)-7-(trimetylsilyl )-l,2,4-triazolo[4,3-b]pyridazin (5,0 g, 15,6 mmol), fremstilt som beskrevet i eksempel 25, trinn c), og 1,2-dijod-et an (14 g, 50 mmol) i 150 ml vannfri THF, ble tilsatt via kanyle til en omrørt suspensjon av tris(dimetylamino)svovel-(trimetylsilyl)difluorid (5,0 g, 18 mmol) i 200 ml vannfri THF ved romtemperatur under nitrogen. Etter 18 t ble blandingen fortynnet med 400 ml diklormetan og ble vasket sekvensvis med 300 ml vann og 200 ml saltvann. Det organiske lag ble tørket (Na2S04), filtrert og konsentrert. Flashkolonnekromatografi på silikagel og eluering med 3 % metanol-diklormetan ga urent 6-klor-3-(2-fluorfenyl)-7-jod-1,2,4-triazolo[4,3-b]pyridazin (3,54 g) som et mørkebrunt, fast materiale. Dette ble under-kastet de betingelser som er beskrevet i eksempel 27, trinn A solution of 6-chloro-3-(2-fluorophenyl)-7-(trimethylsilyl)-1,2,4-triazolo[4,3-b]pyridazine (5.0 g, 15.6 mmol), prepared as described in Example 25, step c), and 1,2-diiodo-etane (14 g, 50 mmol) in 150 mL of anhydrous THF was added via cannula to a stirred suspension of tris(dimethylamino)sulfur-(trimethylsilyl)difluoride (5.0 g, 18 mmol) in 200 mL anhydrous THF at room temperature under nitrogen. After 18 h, the mixture was diluted with 400 ml of dichloromethane and was washed sequentially with 300 ml of water and 200 ml of brine. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. Flash column chromatography on silica gel eluting with 3% methanol-dichloromethane gave impure 6-chloro-3-(2-fluorophenyl)-7-iodo-1,2,4-triazolo[4,3-b]pyridazine (3.54 g) as a dark brown, solid material. This was subjected to the conditions described in example 27, step

b), under dannelse av 3-(2-fluorfenyl)-7-jod-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin b), forming 3-(2-fluorophenyl)-7-iodo-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4, 3-b]pyridazine

(1,32 g, 19 % over to trinn) som et gult, fast materiale; (1.32 g, 19% over two steps) as a yellow solid;

<X>H NMR (360 MHz, CDC13) 6 3,97 (3 H, s), 5,51 (2 H, s), 7,28 (1 H, dd, J = 8 og 8 Hz), 7,37 (1 H, dd, J = 8 og 8 Hz), 7,56-7,64 (1 H, m), 7,86 (1 H, ddd, J = 7, 7 og 1 Hz), 7,90 (1 H, s), 8,68 (1 H, s); <X>H NMR (360 MHz, CDCl 3 ) δ 3.97 (3 H, s), 5.51 (2 H, s), 7.28 (1 H, dd, J = 8 and 8 Hz), 7 .37 (1 H, dd, J = 8 and 8 Hz), 7.56-7.64 (1 H, m), 7.86 (1 H, ddd, J = 7, 7 and 1 Hz), 7 .90 (1H, s), 8.68 (1H, s);

MS (ES<*>) m/e 452 [MH]<*>. MS (ES<*>) m/e 452 [MH]<*>.

b) 7- syklopentylmetyl- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H-1, 2, 4- triazol- 3- ylmetoksy)- 1, 2, 4- triazolo[ 4, 3- b]-pyridazin b) 7- cyclopentylmethyl- 3-( 2- fluorophenyl)- 6-( 2- methyl- 2H-1, 2, 4- triazol- 3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] -pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyren beskrevet i eksempel 27, trinn c), med syklopentyl-metyljodid anvendt i stedet for neopentyljodid og 3-(2-fluorfenyl)-7-j od-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin i stedet for 7-brom-3-(2-fluorfenyl)-6- (2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin. Data for tittelforbindelsen: Smp.: 135-137 °C; This compound was prepared using the procedure described in Example 27, step c), with cyclopentyl methyl iodide substituted for neopentyl iodide and 3-(2-fluorophenyl)-7-iod-6-(2-methyl-2H-1 ,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine instead of 7-bromo-3-(2-fluorophenyl)-6-(2-methyl-2H -1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine. Data for the title compound: mp: 135-137 °C;

<X>H NMR (360 MHz, CDC13) 6 1,18-1,28 (2 H, m), 1,36-1,74 (4 H, m), 1,76-1,86 (2 H, m), 2,16-2,28 (1 H, m), 2,66 <X>H NMR (360 MHz, CDCl 3 ) δ 1.18-1.28 (2H, m), 1.36-1.74 (4H, m), 1.76-1.86 (2H , m), 2.16-2.28 (1H, m), 2.66

(2 H, d, J = 7 Hz), 3,84 (3 H, s), 5,49 (2 H, s) 7,25-7,30 (2 H, d, J = 7 Hz), 3.84 (3 H, s), 5.49 (2 H, s) 7.25-7.30

(1 H, m), 7,36 (1 H, dd, J = 7 og 7Hz), 7,50-7,60 (1 H, m), 7,82-7-86 (2 H, m), 7,89 (1 H, s); (1 H, m), 7.36 (1 H, dd, J = 7 and 7Hz), 7.50-7.60 (1 H, m), 7.82-7-86 (2 H, m) , 7.89 (1H, s);

MS (ES<*>) m/e 382 [MH]<*>; MS (ES<*>) m/e 382 [MH]<*>;

Analyse funnet: C 60,85, H 5,38 % C21H22FN70-0,4 H20 kreves: C 60,83, H 5,54 *. Analysis found: C 60.85, H 5.38% C 21 H 22 FN 70 -0.4 H 2 O required: C 60.83, H 5.54 *.

Eksempel 31 Example 31

7-( 3- benzyloksysyklobutyl)- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H-1, 2, 4- triazol- 3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 7-( 3- benzyloxycyclobutyl)- 3-( 2- fluorophenyl)- 6-( 2- methyl- 2H-1, 2, 4- triazol- 3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

a) cls- 3- benzyloksy- 1- hydroksysyklobutan a) cls- 3- benzyloxy- 1- hydroxycyclobutane

En blanding av 3-benzyloksysyklobutan-l-on (0,92 g, A mixture of 3-benzyloxycyclobutan-1-one (0.92 g,

5,22 mmol) (Ogura et al., Bull. Chem. Soc. Jpn., 1984, 57, 1637-1642) og natriumborhydrid (0,20 g, 5,29 mmol) i 15 ml etanol ble omrørt ved romtemperatur i 3,5 t. Blandingen ble filtrert, ble vasket med etanol og filtratet ble konsentrert. Filtrering gjennom en plugg av silika og eluering med etylacetat, ga cis-3-benzyloksy-l-hydroksysyklobutan (0,854 g, 92 %) som en fargeløs olje; 5.22 mmol) (Ogura et al., Bull. Chem. Soc. Jpn., 1984, 57, 1637-1642) and sodium borohydride (0.20 g, 5.29 mmol) in 15 ml of ethanol were stirred at room temperature in 3.5 h. The mixture was filtered, washed with ethanol and the filtrate was concentrated. Filtration through a plug of silica and eluting with ethyl acetate gave cis-3-benzyloxy-1-hydroxycyclobutane (0.854 g, 92%) as a colorless oil;

<*>H NMR (250 MHz, CDC13) 5 1,75-2,00 (2 H, m), 2,65-2,79 (2 H, m), 3,62 (1 H, qn, J = 7 Hz), 3,90 (1 H, bred qn, <*>H NMR (250 MHz, CDCl 3 ) δ 1.75-2.00 (2 H, m), 2.65-2.79 (2 H, m), 3.62 (1 H, qn, J = 7 Hz), 3.90 (1 H, wide qn,

J - 7 Hz), 4,41 (2 H, s), 7,23-7,47 (5 H, m). J - 7 Hz), 4.41 (2 H, s), 7.23-7.47 (5 H, m).

b) cis- 3- benzyloksy- 1- metansulfonyloksysyklobutan b) cis-3-benzyloxy-1-methanesulfonyloxycyclobutane

Metansulfonylklorid (0,44 ml, 5,7 mmol) ble tilsatt Methanesulfonyl chloride (0.44 mL, 5.7 mmol) was added

dråpevis til en omrørt løsning av cis-3-benzyloksy-l-hydroksysyklobutan (0,85 g, 4,77 mmol) og trietylamin (1,0 ml, dropwise to a stirred solution of cis-3-benzyloxy-1-hydroxycyclobutane (0.85 g, 4.77 mmol) and triethylamine (1.0 mL,

7,2 mmol) i 15 ml tørr diklormetan ved 0 °C under nitrogen. Den hvite suspensjonen ble omrørt ved 0 "C i 1,5 t, ble deretter helt over i 50 ml vann og ble ekstrahert med 2 x 30 ml diklormetan. Ekstraktene ble tørket (Na2S04), filtrert og konsentrert. Oljen ble filtrert gjennom en plugg av silikagel og ble eluert med etylacetat under dannelse av cis-3-benzyloksy-1-metansulfonyloksysyklobutan (1,27 g, 100 %) som en gul olje; 7.2 mmol) in 15 ml of dry dichloromethane at 0 °C under nitrogen. The white suspension was stirred at 0"C for 1.5 h, then poured into 50 mL of water and extracted with 2 x 30 mL of dichloromethane. The extracts were dried (Na 2 SO 4 ), filtered and concentrated. The oil was filtered through a plug of silica gel and was eluted with ethyl acetate to give cis-3-benzyloxy-1-methanesulfonyloxycyclobutane (1.27 g, 100%) as a yellow oil;

<l>H NMR (250 MHz, CDC13) 6 2,26-2,39 (2 H, m), 2,77-2,91 (2 H, m), 2,97 (3 H, s), 3,74 (1 H, qn, J = 7 Hz), 4,42 (2 H, s), 4,68 (1 H, qn, J = 7 Hz), 7,26-7,42 (5 H, m). <1>H NMR (250 MHz, CDCl 3 ) δ 2.26-2.39 (2H, m), 2.77-2.91 (2H, m), 2.97 (3H, s), 3.74 (1 H, qn, J = 7 Hz), 4.42 (2 H, s), 4.68 (1 H, qn, J = 7 Hz), 7.26-7.42 (5 H , m).

c) trans- 3- benzyloksy- l- jodsyklobutan c) trans-3-benzyloxy-1-iodocyclobutane

En løsning av cis-3-benzyloksy-l-metansulfonyloksysyklobutan (1,25 g, 4,8 mmol) og natriumjodid (2,16 g, A solution of cis-3-benzyloxy-1-methanesulfonyloxycyclobutane (1.25 g, 4.8 mmol) and sodium iodide (2.16 g,

14,4 mmol) i 20 ml tørr aceton ble kokt under tilbakeløps-kjøling under nitrogen i 3,5 dager. Blandingen ble avkjølt og ble fortynnet med 150 ml dietyleter. Suspensjonen ble filtrert og filtratet ble konsentrert. Residuet ble oppløst i etylacetat og ble filtrert gjennom en plugg av silikagel og ble elu- 14.4 mmol) in 20 mL of dry acetone was refluxed under nitrogen for 3.5 days. The mixture was cooled and diluted with 150 ml of diethyl ether. The suspension was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and filtered through a plug of silica gel and eluted

ert med etylacetat under dannelse av trans-3-benzyloksy-l-jodsyklobutan (1,19 g, 86 %) som en orange olje; pea with ethyl acetate to give trans-3-benzyloxy-1-iodocyclobutane (1.19 g, 86%) as an orange oil;

<X>HNMR (250 MHz, CDC13) 5 2,54-2,65 (2 H, m), 2,94-3,04 (2 H, m), 3,85-4,06 (2 H, m), 4,40 (2 H, s), 7,26-7,38 <X>HNMR (250 MHz, CDC13) 5 2.54-2.65 (2H, m), 2.94-3.04 (2H, m), 3.85-4.06 (2H, m), 4.40 (2H, s), 7.26-7.38

(5 H, m). (5 H, m).

d) 7-( 3- benzyloksysyklobutyl)- 3-( 2- fluorfenyl)- 6-( 2-metyl- 2H- 1, 2, 4- triazolo[ 4, 3- blpyridazin d) 7-( 3- benzyloxycyclobutyl)- 3-( 2- fluorophenyl)- 6-( 2-methyl- 2H- 1, 2, 4- triazolo[ 4, 3- blpyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyren beskrevet i eksempel 27, trinn c), med trans-3-benzyloksy- 1-jodsyklobutan anvendt i stedet for neopentyljodid. Forbindelsen ble isolert ved preparativ tynnsjiktskromatografi og eluering med 5 % metanol-diklormetan, deretter en andre preparativ tynnsjiktskromatografi og eluering med 2 % etanol-etylacetat, og triturering med dietyleter under dannelse av en 2,3:1-blanding av trans:cis-isomerer; This compound was prepared using the procedure described in Example 27, step c), with trans-3-benzyloxy-1-iodocyclobutane used instead of neopentyl iodide. The compound was isolated by preparative thin-layer chromatography eluting with 5% methanol-dichloromethane, then a second preparative thin-layer chromatography eluting with 2% ethanol-ethyl acetate, and trituration with diethyl ether to give a 2.3:1 mixture of trans:cis isomers ;

<*>H NMR (360 MHz, CDC13) 8 2,00-2,10 og 2,18-2,26 <*>H NMR (360 MHz, CDCl 3 ) δ 2.00-2.10 and 2.18-2.26

(2 H, m), 2,28-2,38 og 2,34-2,42 (2 H, m), 3,00-3,10 og 3,68-3,78 (1 H, m), 3,80 og 3,81 (3 H, s), 4,02-4,22 (1 H, m), 4,46 og 4,47 (2 H, s), 5,46 og 5,47 (2 H, s), 7,24-7,37 (7 H, m), 7,56-7,60 (1 H, m), 7,80-7,91 (3 H, m); (2 H, m), 2.28-2.38 and 2.34-2.42 (2 H, m), 3.00-3.10 and 3.68-3.78 (1 H, m) , 3.80 and 3.81 (3 H, s), 4.02-4.22 (1 H, m), 4.46 and 4.47 (2 H, s), 5.46 and 5.47 (2H, s), 7.24-7.37 (7H, m), 7.56-7.60 (1H, m), 7.80-7.91 (3H, m);

MS (ES<+>) m/e 486 [MH]<+>. MS (ES<+>) m/e 486 [MH]<+>.

Eksempel 32 Example 32

3- ( 2- fluorfenyl)- 7-( 3- hydroksysyklobutyl)- 6-( 2- metyl- 2H- 1, 2, 4-triazol- 3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 3-( 2- fluorophenyl)- 7-( 3- hydroxycyclobutyl)- 6-( 2- methyl- 2H- 1, 2, 4-triazol- 3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

En blanding av 7-(3-benzyloksysyklobutyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo [4, 3-b] pyridazin (0,04 g, 0,082 mmol), overskudd av ammoniumformiat (1,0 g) 1 ml maursyre og 0,10 g 10 % palladium på karbon ble omrørt ved 60 °C under nitrogen i 18 t og ble deretter avkjølt og konsentrert. Residuet ble fortynnet med 20 ml diklormetan og ble vasket med 20 ml saltvann. Det organiske lag ble tørket (Na2S04), filtrert og konsentrert. Preparativ tynnsjiktskromatografi på silikagel og eluering med 10 % metanol -diklormetan ga gjenvunnet 7-(3-benzyloksysyklobutyl)-3-{2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin (0,016 g, 40 %) og 3-(2-fluorfenyl)-7-(3-hydroksysyklobuty1)-6-(2-metyl-2H-1,2,4-triazol-3-yl- metoksy)-l,2,4-triazolo[4,3-b]pyridazin (0,009 g, 28 %) som et hvitt, fast materiale som en 3:l-blanding av trans:cis-isomerer:<X>H NMR (360 MHz, CDC13) 5 2,08-2,18, 2,36-2,56 og 2,70-2,84 (4 H, m), 3,00-3,08 og 3,70-3,78 (1 H, m), 3,82 A mixture of 7-(3-benzyloxycyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4 , 3-b] pyridazine (0.04 g, 0.082 mmol), excess ammonium formate (1.0 g), 1 mL of formic acid, and 0.10 g of 10% palladium on carbon were stirred at 60 °C under nitrogen for 18 h and was then cooled and concentrated. The residue was diluted with 20 ml of dichloromethane and was washed with 20 ml of brine. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated. Preparative thin-layer chromatography on silica gel and elution with 10% methanol-dichloromethane gave recovered 7-(3-benzyloxycyclobutyl)-3-{2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy )-1,2,4-triazolo[4,3-b]pyridazine (0.016 g, 40%) and 3-(2-fluorophenyl)-7-(3-hydroxycyclobuty1)-6-(2-methyl-2H- 1,2,4-triazol-3-yl-methoxy)-1,2,4-triazolo[4,3-b]pyridazine (0.009 g, 28%) as a white solid as a 3:1 mixture of trans:cis isomers:<X>H NMR (360 MHz, CDCl 3 ) δ 2.08-2.18, 2.36-2.56 and 2.70-2.84 (4 H, m), 3 .00-3.08 and 3.70-3.78 (1 H, m), 3.82

(3 H, s), 4,36-4,40 og 4,44-4,58 (1 H, m), 5,47 (2 H, s), 7,24-7,32 (1 H, m), 7,43-7,40 (1 H, m), 7,54-7,60 (1 H, m), 7,82-7,96 (3 H, rn); (3 H, s), 4.36-4.40 and 4.44-4.58 (1 H, m), 5.47 (2 H, s), 7.24-7.32 (1 H, m), 7.43-7.40 (1H, m), 7.54-7.60 (1H, m), 7.82-7.96 (3H, rn);

MS (ES<+>) m/e 396 [MH]\ MS (ES<+>) m/e 396 [MH]\

Eksempel 33&34 Example 33&34

7-( l- fluorbut- 3- enyl)- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4-triazol- 3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin og 7-( 3-fluorsyklobutyl)- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol-3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 7-(1-fluorobut-3-enyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[ 4, 3- b] pyridazine and 7-( 3-fluorocyclobutyl)- 3-( 2- fluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol-3- ylmethoxy)- 1, 2, 4-triazolo[4,3-b]pyridazine

Dietylaminosvoveltrifluorid (0,025 ml, 0,17 mmol) ble dråpevis tilsatt ved -78 °C til en omrørt løsning av 3-(2-fluorfenyl)-7-(3-hydroksysyklobutyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin (0,033 g, 0,083 mmol) i 3 ml tørr diklormetan under nitrogen. Etter 3,5 t ved -78 °C ble ytterligere dietylaminosvoveltrifluorid (0,025 ml, 0,17 mmol) tilsatt. Blandingen ble omrørt ved -78 °C i ytterligere 1,25 t, ble oppvarmet til 0 °C over en 10 min periode og reaksjonen ble stanset ved tilsetning av 2 ml metanol. Blandingen ble fortynnet med 20 ml vann og ble ekstrahert med 2 x 20 ml diklormetan. Ekstraktene ble tørket (Na2S04), filtrert og konsentrert. Preparativ tynnsjiktskromatografi på silikagel og eluering med 5 % metanol-diklormetan, ga to produkter. Det mindre polare materialet var 7-(1-fluorbut-3-enyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-yl-metoksy)-1,2,4-triazolo[4,3-b]pyridazin (0,0023 g, 7 %); Diethylaminosulfur trifluoride (0.025 mL, 0.17 mmol) was added dropwise at -78 °C to a stirred solution of 3-(2-fluorophenyl)-7-(3-hydroxycyclobutyl)-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (0.033 g, 0.083 mmol) in 3 mL of dry dichloromethane under nitrogen. After 3.5 h at -78 °C, additional diethylaminosulfur trifluoride (0.025 mL, 0.17 mmol) was added. The mixture was stirred at -78 °C for a further 1.25 h, was warmed to 0 °C over a 10 min period and the reaction was quenched by the addition of 2 ml of methanol. The mixture was diluted with 20 ml of water and was extracted with 2 x 20 ml of dichloromethane. The extracts were dried (Na 2 SO 4 ), filtered and concentrated. Preparative thin layer chromatography on silica gel and eluting with 5% methanol-dichloromethane gave two products. The less polar material was 7-(1-fluorobut-3-enyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-yl-methoxy)-1 ,2,4-triazolo[4,3-b]pyridazine (0.0023 g, 7%);

<*>H NMR (400 MHz, CDC13) 8 2,59-2,87 (2 H, m), 3,85 <*>H NMR (400 MHz, CDCl 3 ) δ 2.59-2.87 (2 H, m), 3.85

(3 H, s), 5,13 (1 H, d, J = 18 Hz), 5,16 (1 H, d, J = 10 Hz), 5,30 (2 H, s), 5,49 (1 H, d, J = 13 Hz), 5,54 (1 H, d, J = 13 Hz), 5,64-5,85 (2 H, m), 7,29 (1 H, ddd, J = 8,8 og 1 Hz), 7,35-7,40 (1 H, m), 7,55-7,62 (1 H, m), 7,84 (1 H, dd, J = 8 og 8 Hz), 7,80 (1 H, s), 8,15 (1 H, s); (3 H, s), 5.13 (1 H, d, J = 18 Hz), 5.16 (1 H, d, J = 10 Hz), 5.30 (2 H, s), 5.49 (1 H, d, J = 13 Hz), 5.54 (1 H, d, J = 13 Hz), 5.64-5.85 (2 H, m), 7.29 (1 H, ddd, J = 8.8 and 1 Hz), 7.35-7.40 (1 H, m), 7.55-7.62 (1 H, m), 7.84 (1 H, dd, J = 8 and 8 Hz), 7.80 (1 H, s), 8.15 (1 H, s);

MS (ES<+>) m/e 398 [MH]<+>. MS (ES<+>) m/e 398 [MH]<+>.

Det mer polare materialet var 7-(3-fluorsyklobutyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin (0,0014 g, 4 %) som en 1:1-blanding av trans:cis-isomerer; The more polar material was 7-(3-fluorocyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazol [4,3-b]pyridazine (0.0014 g, 4%) as a 1:1 mixture of trans:cis isomers;

<X>H NMR (400 MHz, CDC13) 6 2,25-3,10 (4 H, m), 3,81 og 3,82 (3 H, s), 4,13-4,75 (1 H, m), 4,96-5,27 (1 H, m), 5,48 og 5,49 (2 H, s), 7,26-7,30 (1 H, m), 7,36 (1 H, ddd, J = 8,8 og 1 Hz), 7,55-7,60 (1 H, m), 7,79-7,91 (3 H, m); <X>H NMR (400 MHz, CDCl 3 ) δ 2.25-3.10 (4 H, m), 3.81 and 3.82 (3 H, s), 4.13-4.75 (1 H , m), 4.96-5.27 (1 H, m), 5.48 and 5.49 (2 H, s), 7.26-7.30 (1 H, m), 7.36 ( 1 H, ddd, J = 8.8 and 1 Hz), 7.55-7.60 (1 H, m), 7.79-7.91 (3 H, m);

MS (ES<+>) m/e 398 [MH]\ MS (ES<+>) m/e 398 [MH]\

Eksempel 35 Example 35

3- ( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- trlazol- 3- ylmetoksy)- 7-trifluormetyl- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 3-(2-Fluorophenyl)-6-(2-methyl-2H-1,2,4-trilazol-3-ylmethoxy)-7-trifluoromethyl-1,2,4-triazolo[4,3-b]pyridazine

Jodtrifluormetan (2,0 g, 10 mmol) ble boblet gjennom en løsning av 7-brom-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin (0,10 g, 0,25 mmol) i 2 ml tørr DMF ved romtemperatur inntil den nød-vendige mengde av gass var oppløst. Kopperpulver (0,16 g, Iodotrifluoromethane (2.0 g, 10 mmol) was bubbled through a solution of 7-bromo-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)- 1,2,4-triazolo[4,3-b]pyridazine (0.10 g, 0.25 mmol) in 2 mL of dry DMF at room temperature until the required amount of gas was dissolved. Copper powder (0.16 g,

2,5 mmol) ble tilsatt, og blandingen ble omrørt i et forseglet rør ved 80 °C i 18 t. Blandingen ble avkjølt, ble fortynnet med 50 ml diklormetan og filtrert. Filtratet ble vasket med 50 ml vann, ble deretter tørket (Na2S04), filtrert og konsentrert. Preparativ tynnsjiktskromatografi og eluering med 3 % metanol-diklormetan, ga 3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-7-trifluormetyl-1,2,4-triazolo[4,3-b]pyridazin (0,0061 g, 6 %) som et blekt gult, fast materiale; 2.5 mmol) was added and the mixture was stirred in a sealed tube at 80 °C for 18 h. The mixture was cooled, diluted with 50 ml of dichloromethane and filtered. The filtrate was washed with 50 mL water, then dried (Na 2 SO 4 ), filtered and concentrated. Preparative thin-layer chromatography and elution with 3% methanol-dichloromethane gave 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-trifluoromethyl-1,2, 4-triazolo[4,3-b]pyridazine (0.0061 g, 6%) as a pale yellow solid;

Smp.: 123-126 °C; M.p.: 123-126 °C;

<*>H NMR (360 MHz, CDC13) 8 3,92 (3 H, s), 5,60 (2 H, s), 7,31 (1 H, dd, J = 8 og 8 Hz), 7,40 (1 H, dd, J - 8 og 8 Hz), 7,56-7,64 (1 H, m), 7,86-7,94 (2 H, m), 8,50 (1 H, s); <*>H NMR (360 MHz, CDCl 3 ) δ 3.92 (3 H, s), 5.60 (2 H, s), 7.31 (1 H, dd, J = 8 and 8 Hz), 7 .40 (1 H, dd, J - 8 and 8 Hz), 7.56-7.64 (1 H, m), 7.86-7.94 (2 H, m), 8.50 (1 H , s);

MS (ES<+>) m/e 393 [MH]\ MS (ES<+>) m/e 393 [MH]\

Eksempel 36 Example 36

3-( 2- fluorfenyl)- 7-( 4- metyltetrahydropyran- 4- yl)- 6-( 2- metyl-2H- 1, 2, 4- triazol- 3- ylmetoksy)- lf 2r 4- triazolo[ 4, 3- b] pyridazin 3-( 2- fluorophenyl)- 7-( 4- methyltetrahydropyran-4- yl)- 6-( 2- methyl-2H- 1, 2, 4- triazol- 3- ylmethoxy)- lf 2r 4- triazolo[ 4, 3- b] pyridazine

a) 4- Metyltetrahydropyran- 4- karboksylsyre a) 4- Methyltetrahydropyran- 4- carboxylic acid

n-Butyllitium (21,1 ml, 33,8 mmol, 1,6 M i heksan) n-Butyl lithium (21.1 mL, 33.8 mmol, 1.6 M in hexane)

ble dråpevis tilsatt i løpet av 10 min til en omrørt løsning av diisopropylamin (4,7 ml, 33,8 mmol) i 40 ml vannfri tetra- was added dropwise over 10 min to a stirred solution of diisopropylamine (4.7 mL, 33.8 mmol) in 40 mL of anhydrous tetra-

hydrofuran under en nitrogenatmosfære ved <10 °C. Etter tilsetningen ble tetrahydropyran-4-karboksylsyre (J. Am. Chem. Soc, 1993, 115, 8407) tilsatt i 20 ml vannfri tetrahydrofuran under nitrogen ved <5 °C. Blandingen ble omrørt ved romtemperatur i 1 t, hvorpå metyljodid (2,4 ml, 38,4 mmol) ble dråpevis tilsatt ved <5 °C. Den resulterende løsning ble omrørt ved <5 °C i 30 min, fikk oppvarmes til romtemperatur og ble omrørt i ytterligere 3,5 dager. Løsningsmidlet ble fjernet ved fordampning og residuet ble oppløst i 100 ml diklormetan og 100 ml 2 N saltsyre ble tilsatt. Det vandige lag ble ekstrahert med 3 x 100 ml diklormetan, og de kombinerte organiske lag ble vasket med 100 ml vann, 100 ml saltvann, ble tørket (MgS04), filtrert og fordampet under dannelse av tittelproduktet (1,4 g) som ble anvendt i neste trinn uten rensing. Data for tittelforbindelsen:<*>H NMR (250 MHz, CDC13) 8 1,00 (3 H, s), 1,47-1,58 hydrofuran under a nitrogen atmosphere at <10 °C. After the addition, tetrahydropyran-4-carboxylic acid (J. Am. Chem. Soc, 1993, 115, 8407) was added in 20 ml of anhydrous tetrahydrofuran under nitrogen at <5 °C. The mixture was stirred at room temperature for 1 h, after which methyl iodide (2.4 mL, 38.4 mmol) was added dropwise at <5 °C. The resulting solution was stirred at <5 °C for 30 min, allowed to warm to room temperature and stirred for an additional 3.5 days. The solvent was removed by evaporation and the residue was dissolved in 100 ml of dichloromethane and 100 ml of 2 N hydrochloric acid was added. The aqueous layer was extracted with 3 x 100 mL dichloromethane and the combined organic layers were washed with 100 mL water, 100 mL brine, dried (MgSO 4 ), filtered and evaporated to give the title product (1.4 g) which was used in the next step without purification. Data for the title compound:<*>H NMR (250 MHz, CDCl 3 ) δ 1.00 (3 H, s), 1.47-1.58

(2 H, m), 2,06-2,11, (2 H, m), 3,49-3,60 (2 H, m), 3,78-3,86 (2 H, m). (2H, m), 2.06-2.11, (2H, m), 3.49-3.60 (2H, m), 3.78-3.86 (2H, m).

b) 3-( 2- fluorfenyl)- 7-( 4- metyltetrahydropyran- 4- yl)- 6-( 2- metyl- 2H- l, 2, 4- trlazol- 3- ylmetoksy)- 1, 2, 4- triazolo [ 4, 3- b] pyridazin b) 3-( 2- fluorophenyl)- 7-( 4- methyltetrahydropyran-4- yl)- 6-( 2- methyl- 2H- 1, 2, 4- trilazol- 3-ylmethoxy)- 1, 2, 4- triazolo [4,3-b]pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyren beskrevet i eksempel 1, trinn a), b) og c), under anvendelse av 4-metyltetrahydropyran-4-karboksylsyre i stedet for syklobutankarboksylsyre i trinn a). Data for tittelforbindelsen: Smp.: 191 °C; This compound was prepared using the procedure described in Example 1, steps a), b) and c), using 4-methyltetrahydropyran-4-carboxylic acid instead of cyclobutanecarboxylic acid in step a). Data for the title compound: mp: 191 °C;

<X>H NMR (360 MHz, CDC13) 8 1,46 (3 H, s), 1,89-1,94 <X>H NMR (360 MHz, CDCl 3 ) δ 1.46 (3 H, s), 1.89-1.94

(2 H, m), 2,07-2,15 (2 H, m), 3,73-3,79 (7 H, m), 5,51 (2 H, s), 7,28-7,30 (1 H, m), 7,36 (1 H, t, J = 7,6 Hz), 7,57 (1 H, m), 7,84 (1 H, m), 7,88 (1 H, s), 7,95 (1 H, s); (2 H, m), 2.07-2.15 (2 H, m), 3.73-3.79 (7 H, m), 5.51 (2 H, s), 7.28-7 .30 (1 H, m), 7.36 (1 H, t, J = 7.6 Hz), 7.57 (1 H, m), 7.84 (1 H, m), 7.88 ( 1 H, p), 7.95 (1 H, p);

MS (ES<+>) m/e 424 [MH]<+>; MS (ES<+>) m/e 424 [MH]<+>;

Analyse funnet: C 59,40, H 5,11, N 23,13 % Analysis found: C 59.40, H 5.11, N 23.13%

C21H„FN702 kreves: C 59,57, H 5,24, N 23,15 %. C21H„FN702 required: C 59.57, H 5.24, N 23.15%.

Eksempel 37 Example 37

3-( 2- fluorfenyl )- 7-( 4- metyltetrahydropyran- 4- yl)- 6-( 1- metyl-1H- 1, 2, 4- triazol- 3- ylmetoksy)- 1, 2, 4- triazolo[ 4, 3- blpyrldazin 3-( 2- fluorophenyl )- 7-( 4- methyltetrahydropyran-4- yl)- 6-( 1- methyl-1H- 1, 2, 4- triazol- 3-ylmethoxy)- 1, 2, 4- triazolo[ 4, 3-blpyrldazine

Denne forbindelse ble fremstilt under anvendelse av prosedyren beskrevet i eksempel 1, trinn a), b) og c), under anvendelse av 4-metyltetrahYdropYran-4-karboksYlsYre (^fremstilt under betingelsene beskrevet i eksempel 36, trinn a)] 1 stedet for syklobutankarboksylsyre i trinn a), og (1-metyl-lH-1,2,4-triazol-3-yl)metanol (fremstilt under anvendelse av betingelsene beskrevet i EP-A-421210) i stedet for (2-metyl-2H-1,2,4-triazol-3-yl)metanol i trinn c). Data for tittelforbindelsen: Smp.: 154 °C; This compound was prepared using the procedure described in Example 1, steps a), b) and c), using 4-methyltetrahydrofuran-4-carboxYlsYre (^prepared under the conditions described in Example 36, step a)] 1 instead of cyclobutanecarboxylic acid in step a), and (1-methyl-1H-1,2,4-triazol-3-yl)methanol (prepared using the conditions described in EP-A-421210) in place of (2-methyl-2H -1,2,4-triazol-3-yl)methanol in step c). Data for the title compound: mp: 154 °C;

<*>H NMR (250 MHz, CDC13) 8 1,46 (3 H, s), 1,93-1,99 <*>H NMR (250 MHz, CDCl 3 ) δ 1.46 (3 H, s), 1.93-1.99

(2 H, m), 2,09-2,20 (2 H, m), 3,77-3,80 (4 H, m), 3,93 (3 H,S), 5,44 (2 H, s), 7,23-7,37 (2 H, ra), 7,49-7,58 (1 H, m), 7,91 (1 H, s), 7,97 (1 H, m), 8,04 (1 H, s); (2 H, m), 2.09-2.20 (2 H, m), 3.77-3.80 (4 H, m), 3.93 (3 H,S), 5.44 (2 H, s), 7.23-7.37 (2 H, ra), 7.49-7.58 (1 H, m), 7.91 (1 H, s), 7.97 (1 H, m), 8.04 (1H, s);

MS (ES<*>) m/e 424 [MH]<*>; MS (ES<*>) m/e 424 [MH]<*>;

Analyse funnet: C 59,26, H 5,22, N, 22,79 % Analysis found: C 59.26, H 5.22, N, 22.79%

C21H22FN702kreves: C 59,57, H 5,24, N, 23,15 %. C 21 H 22 FN 7 O 2 required: C 59.57, H 5.24, N, 23.15%.

Eksempel 38 & 39 Example 38 & 39

7-( 4, 4- difluor- 1- metylsykloheksyl)- 3-( 2- fluorfenyl)- 6-( 2-metyl- 2H- 1, 2, 4- triazol- 3- ylmetoksy)- 1, 2, 4- triazolo[ 4, 3- b]-pyridazin og 7-( 4- fluor- l- metylsykloheks- 3- enyl)- 3-( 2- fluorfenyl )- 6-( 2- metyl- 2H- l, 2, 4- triazol- 3- ylmetoksy)- 1, 2, 4- trla-zolo[ 4, 3- b] pyridazin 7-( 4, 4- difluoro- 1- methylcyclohexyl)- 3-( 2- fluorophenyl)- 6-( 2-methyl- 2H- 1, 2, 4- triazol- 3-ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b ]-pyridazine and 7-( 4- fluoro- 1- methylcyclohex- 3-enyl)- 3-( 2- fluorophenyl )- 6-( 2- methyl- 2H- 1, 2, 4- triazol- 3- ylmethoxy)- 1, 2, 4- trla-zolo[ 4, 3- b] pyridazine

a) 3, 6- diklor- 4-( l- metyl- 4- oksosykloheksyl) pyridazin a) 3, 6-dichloro-4-(1-methyl-4-oxocyclohexyl)pyridazine

Denne forbindelse ble fremstilt under anvendelse av This compound was prepared using

prosedyren beskrevet i eksempel 1, trinn a), under anvendelse av l-metyl-4-oksosykloheksankarboksylsyre (Aust. J. Chem., 1970, 23, 1005) i stedet for syklobutankarboksylsyre. Data for tittelforbindelsen:<X>H NMR (360 MHz, CDC13) 8 1,63 (3 H, s) 2,23-2,38 the procedure described in Example 1, step a), using 1-methyl-4-oxocyclohexanecarboxylic acid (Aust. J. Chem., 1970, 23, 1005) instead of cyclobutanecarboxylic acid. Data for the title compound: <X>H NMR (360 MHz, CDCl 3 ) δ 1.63 (3 H, s) 2.23-2.38

(4 H, m), 2,46-2,55 (4 H, m), 7,51 (1 H, s); (4H, m), 2.46-2.55 (4H, m), 7.51 (1H, s);

MS (ES<*>) m/e 261 [MH]<*>. MS (ES<*>) m/e 261 [MH]<*>.

b) 3, 6- diklor- 4-( 4, 4- difluor- 1- metylsykloheksyl) pyridazin og 3, 6- diklor- 4-( 4- fluor- l- metylsykloheks- 3-enyl) pyridazin b) 3, 6- dichloro- 4-( 4, 4- difluoro- 1- methylcyclohexyl) pyridazine and 3, 6- dichloro- 4-( 4- fluoro- 1- methylcyclohex- 3-enyl) pyridazine

En løsning av dietylaminosvoveltrifluorid (1,2 ml, A solution of diethylaminosulfur trifluoride (1.2 ml,

9,13 mmol) i 60 ml vannfri diklormetan under en nitrogenatmosfære ved -78 °C, ble tilsatt til en løsning av 3,6-diklor-4-( 1-metyl-4-oksosykloheksyl)pyridazin (1,08 g, 4,15 mmol) i 140 ml vannfri diklormetan under nitrogen ved -78 °C. Reaksjonsblandingen fikk oppvarmes langsomt til romtemperatur og ble omrørt i 5,5 dager. Reaksjonsblandingen ble helt over i 250 ml mettet natriumbikarbonat og is, ble separert, og det vandige lag ble ekstrahert med 2 x 50 ml diklormetan, de organiske lag ble kombinert, ble vasket med 250 ml saltvann, tørket (MgS04), filtrert og fordampet under dannelse av det urene produkt som ble renset ved kromatografi på silikagel og eluert med 0 %->20 % etylacetat/heksan under dannelse av tittelforbindelsen (0,82 g, 70 %) som en blanding i forholdet 2,7:1. Data for tittelforbindelsene:<2>H NMR (360 MHz, CDC13) 5 1,50 (2,2 H, s), 1,54 9.13 mmol) in 60 mL of anhydrous dichloromethane under a nitrogen atmosphere at -78 °C was added to a solution of 3,6-dichloro-4-(1-methyl-4-oxocyclohexyl)pyridazine (1.08 g, 4 .15 mmol) in 140 ml of anhydrous dichloromethane under nitrogen at -78 °C. The reaction mixture was allowed to warm slowly to room temperature and was stirred for 5.5 days. The reaction mixture was poured into 250 mL saturated sodium bicarbonate and ice, separated, and the aqueous layer was extracted with 2 x 50 mL dichloromethane, the organic layers were combined, washed with 250 mL brine, dried (MgSO 4 ), filtered and evaporated under giving the crude product which was purified by chromatography on silica gel eluting with 0%->20% ethyl acetate/hexane to give the title compound (0.82g, 70%) as a 2.7:1 mixture. Data for the title compounds:<2>H NMR (360 MHz, CDCl 3 ) δ 1.50 (2.2 H, s), 1.54

(0,8 H, s), 1,84-2,79 (7,3 H, m), 5,20-5,29 (0,2 H, m), 7,38 (0,2 H, s), 7,46 (0,8 H, s); (0.8 H, s), 1.84-2.79 (7.3 H, m), 5.20-5.29 (0.2 H, m), 7.38 (0.2 H, s), 7.46 (0.8H, s);

MS (ES<*>) m/e 282 [MH]<*>og m/e 262 [MH]<*>. MS (ES<*>) m/e 282 [MH]<*>and m/e 262 [MH]<*>.

c) 7-( 4, 4- difluor- 1- metylsykloheksyl)- 3-{ 2- fluorfenyl)-6-( 2- metyl- 2H- l, 2, 4- triazol- 3- ylmetoksy)- 1, 2, 4- triazolo [ 4, 3- b] pyridazin og 7-( 4- fluor- l- metylsykloheks-3- enyl)- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol-3- ylmetoksy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin c) 7-(4,4-difluoro-1-methylcyclohexyl)-3-{2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2, 4-triazolo[4,3-b]pyridazine and 7-(4-fluoro-1-methylcyclohex-3-enyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4 - triazol-3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3-b] pyridazine

Tittelforbindelsene ble fremstilt under anvendelse av prosedyren beskrevet i eksempel 1, trinn b) og c), under anvendelse av en blanding av 3,6-diklor-4-(4,4-difluor-l-metylsykloheksyl)pyridazin og 3,6-diklor-4-(4-fluor-1-metylsykloheks-3-enyl)pyridazin i stedet for 3,6-diklor-4-syklobutylpyridazin i trinn b). Forbindelsene ble separert ved HPLC. Data for 7-(4,4-difluor-l-metylsykloheksyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin: Smp.: 135 °C; The title compounds were prepared using the procedure described in Example 1, steps b) and c), using a mixture of 3,6-dichloro-4-(4,4-difluoro-1-methylcyclohexyl)pyridazine and 3,6- dichloro-4-(4-fluoro-1-methylcyclohex-3-enyl)pyridazine instead of 3,6-dichloro-4-cyclobutylpyridazine in step b). The compounds were separated by HPLC. Data for 7-(4,4-difluoro-1-methylcyclohexyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2, 4-triazolo[4,3-b]pyridazine: mp: 135 °C;

<X>H NMR (250 MHZ, CDC13) 5 1,42 (3 H, s), 1,82-2,08 (6 H, m), 2,16-2,34 (2 H, m), 3,78 (3 H, s), 5,53 (2 H, s), 7,25-7,40 (2 H, m), 7,58 (1 H, m), 7,84 (1 H, m), 7,89 (1 H, s), 8,02 (1 H, s); <X>H NMR (250 MHZ, CDCl 3 ) δ 1.42 (3 H, s), 1.82-2.08 (6 H, m), 2.16-2.34 (2 H, m), 3.78 (3 H, s), 5.53 (2 H, s), 7.25-7.40 (2 H, m), 7.58 (1 H, m), 7.84 (1 H , m), 7.89 (1H, s), 8.02 (1H, s);

MS (ES<*>) m/e 458 [MH]<*>; MS (ES<*>) m/e 458 [MH]<*>;

Analyse funnet: C 55,36, H 5,00, N 18,96 % CjjHjjFa^O-0,5 EtOAc-1,0 H20 kreves: C 55,48, H 5,43, N 18,87 %. Analysis found: C 55.36, H 5.00, N 18.96% CjjHjjFa^O-0.5 EtOAc-1.0 H 2 O required: C 55.48, H 5.43, N 18.87%.

Data for 7-(4-fluor-l-metylsykloheks-3-enyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazo1-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin: Smp.: 175 °C; Data for 7-(4-fluoro-1-methylcyclohex-3-enyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazo1-3-ylmethoxy)-1, 2,4-triazolo[4,3-b]pyridazine: mp: 175 °C;

<X>HNMR (360 MHz, CDC13) 8 1,41 (3 H, s), 1,76-1,98 (2 H, m), 2,18-2,58 (4 H, m), 3,78 (3 H, s), 5,21-5,26 (1 H, m), 5,53 (2 H, s), 7,26-7,38 (2 H, m), 7,54-7,59 (1 H, m), 7,84 (1 H, m), 7,89 (1 H, s), 7,95 (1 H, s); <X>HNMR (360 MHz, CDC13) 8 1.41 (3 H, s), 1.76-1.98 (2 H, m), 2.18-2.58 (4 H, m), 3 .78 (3 H, s), 5.21-5.26 (1 H, m), 5.53 (2 H, s), 7.26-7.38 (2 H, m), 7.54 -7.59 (1 H, m), 7.84 (1 H, m), 7.89 (1 H, s), 7.95 (1 H, s);

MS (ES<*>) m/e 438 [MH]<*>. MS (ES<*>) m/e 438 [MH]<*>.

Eksempel 40 Example 40

7- ( 4, 4- difluor- 1- metylsykloheksyl)- 3-( 2- fluorfenyl)- 6-( 1-metyl- lH- 1, 2, 4- triazol- 3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b]-pyridazin 7-( 4, 4- difluoro- 1- methylcyclohexyl)- 3-( 2- fluorophenyl)- 6-( 1-methyl- 1H- 1, 2, 4- triazol- 3-ylmethoxy)- 1, 2, 4- triazolo[4,3-b]-pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyren beskrevet 1 eksempel 38, trinn a), b) og c), under anvendelse av (1-metyl-lH-l,2,4-triazol-3-yl)-metanol [fremstilt under anvendelse av de betingelser som er beskrevet i EP-A-421210) i stedet for (2-metyl-2H-l,2,4-triazol-3-yl)-metanol i trinn c). Data for tittelforbindelsen: Smp.: 193 °C; This compound was prepared using the procedure described in Example 38, steps a), b) and c), using (1-methyl-1H-1,2,4-triazol-3-yl)-methanol [prepared under using the conditions described in EP-A-421210) instead of (2-methyl-2H-1,2,4-triazol-3-yl)-methanol in step c). Data for the title compound: mp: 193 °C;

<l>H NMR (360 MHz, CDCI3) 8 1,43 (3 H, s), 1,88-2,12 (6 H, m), 2,26-2,39 (2 H, m), 3,92 (3 H, s), 5,45 (2 H, s), 7,24-7,35 (2 H, m), 7,51-7,56 (1 H, m), 7,94 (1 H, m), 7,97 (1 H, s), 8,04 (1 H, s); <1>H NMR (360 MHz, CDCl 3 ) δ 1.43 (3 H, s), 1.88-2.12 (6 H, m), 2.26-2.39 (2 H, m), 3.92 (3 H, s), 5.45 (2 H, s), 7.24-7.35 (2 H, m), 7.51-7.56 (1 H, m), 7, 94 (1H, m), 7.97 (1H, s), 8.04 (1H, s);

MS (ES<*>) m/e 458 [MH]<*>; MS (ES<*>) m/e 458 [MH]<*>;

Analyse funnet: C 57,84, H 4,75, N, 21,07 % C22H2zF3N70 kreves: C 57,76, H 4,85, N, 21,43 %. Analysis found: C 57.84, H 4.75, N, 21.07% C22H2zF3N70 required: C 57.76, H 4.85, N, 21.43%.

Eksempel 41 Example 41

3-( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol- 3- ylmetoksy)- 7-( 3- oksosyklobutyl)- 1, 2, 4- triazolo[ 4, 3- b] pyridazin 3-( 2- fluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol- 3- ylmethoxy)- 7-( 3- oxocyclobutyl)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

a) 7-( 3- benzyloksysyklobutyl)- 6- klor- 3-( 2- fluorfenyl)-1, 2, 4- triazolo[ 4, 3- b] pyridazin a) 7-( 3- benzyloxycyclobutyl)- 6- chloro- 3-( 2- fluorophenyl)-1, 2, 4- triazolo[ 4, 3-b] pyridazine

Denne forbindelse ble fremstilt på lignende måte som beskrevet i eksempel 1, trinn a) og b), under anvendelse av 3-benzyloksysyklobutankarboksylsyre (Collect. Czech. Chem. Commun., 1982, 47, 2440) i stedet for syklobutankarboksylsyre. Data for tittelforbindelsen:<1>H NMR (360 MHz, CDC13), cis- og trans-isomerer til stede i 58:1-forhold, 8 2,06-2,51 (2 H, m), 2,63-2,91 (2 H, m), 3,13-3,25 (1 H, m), 3,81-4,25 (1 H, m), 4,50 (2 H, s), 7,28-7,36 (7 H, m), 7,54-7,61 (1 H, m), 7,88 (1 H, m), 7,97 og 8,03 (1 H, 2 s); This compound was prepared in a similar manner as described in Example 1, steps a) and b), using 3-benzyloxycyclobutanecarboxylic acid (Collect. Czech. Chem. Commun., 1982, 47, 2440) instead of cyclobutanecarboxylic acid. Data for the title compound:<1>H NMR (360 MHz, CDCl 3 ), cis and trans isomers present in 58:1 ratio, δ 2.06-2.51 (2 H, m), 2.63- 2.91 (2 H, m), 3.13-3.25 (1 H, m), 3.81-4.25 (1 H, m), 4.50 (2 H, s), 7, 28-7.36 (7 H, m), 7.54-7.61 (1 H, m), 7.88 (1 H, m), 7.97 and 8.03 (1 H, 2 s) ;

MS (ES<+>) m/e 409 [MH]<*>. MS (ES<+>) m/e 409 [MH]<*>.

b) 7-( 3- benzyloksysyklobutyl)- 3-( 2- fluorfenyl)- 1, 2, 4-triazolo[ 4, 3- b] pyridazin- 6- on b) 7-(3-benzyloxycyclobutyl)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazin-6-one

4 N natriumhydroksid (3 ml, 12 mmol) ble tilsatt til en løsning av 7-(3-benzyloksysyklobutyl)-6-klor-3-(2-fluorfenyl )-l, 2, 4-triazolo [4, 3-b] pyridazin (0,98 g, 2,4 mmol) i 30 ml 1,4-dioksan og 8 ml vann og ble oppvarmet til tilbake-løpskoking i 18 t. Løsningsmidlet ble fordampet og residuet ble oppløst i 50 ml dietyleter og 50 ml vann og ble separert. Det vandige lag ble surgjort til pH 2 med 2 N saltsyre og det resulterende, faste materialet ble oppsamlet ved filtrering, ble vasket med 50 ml vann, etterfulgt av 50 ml dietyleter og ble tørket under vakuum ved 100 °C i 18 t. Data for tittelforbindelsen:<*>H NMR (400 MHz, CDC13), cis- og trans-isomerer til stede i 4:l-forhold, 8 1,95-2,03 (1,6 H, m), 2,31-2,38 (0,4 H, m), 2,50-2,56 (0,4 H, m), 2,68-2,76 (1,6, m), 3,05-3,13 (1 H, m), 3,65-3,73 (0,2 H, m), 4,06-4,15 (0,8 H, m), 4,46 (2 H, s), 6,80-6,87 (2 H, m), 7,22-7,37 (6 H, m), 7,55-7,61 (1 H, m), 7,63 (0,8 H, m), 7,68 (0,2 H, s); 4 N sodium hydroxide (3 mL, 12 mmol) was added to a solution of 7-(3-benzyloxycyclobutyl)-6-chloro-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b] pyridazine (0.98 g, 2.4 mmol) in 30 mL of 1,4-dioxane and 8 mL of water and was heated to reflux for 18 h. The solvent was evaporated and the residue was dissolved in 50 mL of diethyl ether and 50 mL of water and were separated. The aqueous layer was acidified to pH 2 with 2 N hydrochloric acid and the resulting solid was collected by filtration, washed with 50 mL of water, followed by 50 mL of diethyl ether, and dried under vacuum at 100 °C for 18 h. Data for the title compound:<*>H NMR (400 MHz, CDCl 3 ), cis and trans isomers present in 4:1 ratio, δ 1.95-2.03 (1.6 H, m), 2.31- 2.38 (0.4 H, m), 2.50-2.56 (0.4 H, m), 2.68-2.76 (1.6, m), 3.05-3.13 (1 H, m), 3.65-3.73 (0.2 H, m), 4.06-4.15 (0.8 H, m), 4.46 (2 H, s), 6 .80-6.87 (2 H, m), 7.22-7.37 (6 H, m), 7.55-7.61 (1 H, m), 7.63 (0.8 H, m), 7.68 (0.2 H, s);

MS (ES<*>) m/e 391 [MH]<*>. MS (ES<*>) m/e 391 [MH]<*>.

c) 3-( 2- fluorfenyl)- 7-( 3- hydroksysyklobutyl)- 1, 2, 4-triazolo[ 4, 3- b] pyridazin- 6- on c) 3-(2-fluorophenyl)-7-(3-hydroxycyclobutyl)-1,2,4-triazolo[4,3-b]pyridazin-6-one

8 ml maursyre ble tilsatt til en løsning av 7-(3-benzyloksysyklobutyl)-3-(2-fluorfenyl)-l,2,4-triazolo[4,3-b]-pyridazin-6-on (0,64 g, 1,64 mmol) og ammoniumformiat (1,034 g, 16,4 mmol) i 40 ml metanol. Løsningen ble spylt med nitrogen og 0,3 g 10 % palladium på karbon ble tilsatt. Den resulterende løsning ble omrørt under en nitrogenatmosfære i 2 t ved 60 °C. Reaksjonsblandingen ble avkjølt, ble filtrert og konsentrert under vakuum. Residuet ble renset ved kromatografi på silika under anvendelse av 0-10 % metanol/diklormetan som elueringsmiddel, under dannelse av det ønskede produkt som et hvitt, fast materiale. Data for tittelforbindelsen:<X>H NMR (360 MHz, DMS0), cis- og trans-isomerer til stede i 5,5:1-forhold, 8 1,89-1,98 (1,7 H, m), 2,21-2,29 8 ml of formic acid was added to a solution of 7-(3-benzyloxycyclobutyl)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]-pyridazin-6-one (0.64 g , 1.64 mmol) and ammonium formate (1.034 g, 16.4 mmol) in 40 mL of methanol. The solution was flushed with nitrogen and 0.3 g of 10% palladium on carbon was added. The resulting solution was stirred under a nitrogen atmosphere for 2 h at 60 °C. The reaction mixture was cooled, filtered and concentrated under vacuum. The residue was purified by chromatography on silica using 0-10% methanol/dichloromethane as eluent to give the desired product as a white solid. Data for the title compound: <X>H NMR (360 MHz, DMS0), cis and trans isomers present in 5.5:1 ratio, δ 1.89-1.98 (1.7 H, m), 2.21-2.29

(0,3 H, m), 2,40-2,48 (0,3 H, m), 2,55-2,65 (1,7 H, m), 2,88-3,00 (1 H, m), 4,06-4,14 (0,85 H, m), 4,20-4,30 (0,15 H, m), 7,38-7,47 (2 H, m), 7,60-7,65 (1 H, m), 7,80-7,85 (1 H, m), 7,97 (0,85 H, s), 8,12 (0,15 H, s); (0.3 H, m), 2.40-2.48 (0.3 H, m), 2.55-2.65 (1.7 H, m), 2.88-3.00 (1 H, m), 4.06-4.14 (0.85 H, m), 4.20-4.30 (0.15 H, m), 7.38-7.47 (2 H, m) , 7.60-7.65 (1 H, m), 7.80-7.85 (1 H, m), 7.97 (0.85 H, s), 8.12 (0.15 H, s);

MS (ES<*>) m/e 301 [MH]<*.>MS (ES<*>) m/e 301 [MH]<*.>

d) 3-( 2- fluorfenyl)- 7-( 3- oksosyklobutyl)- 1, 2, 4- triazolo-[ 4, 3- b] pyridazin- 6- on d) 3-(2-fluorophenyl)-7-(3-oxocyclobutyl)-1,2,4-triazolo-[4,3-b]pyridazin-6-one

8 N kromsyre ble tilsatt til en løsning av 3-(2-fluorfenyl)-7-(3-hydroksysyklobutyl)-l,2,4-triazolo[4,3-b]-pyridazin-6-on (0,36 g, 1,2 mmol) i 50 ml aceton, dråpevis inntil overskudd var til stede (rød farge vedvarte). Reaksjonsblandingen ble deretter omrørt i 2 t før isopropanol ble tilsatt inntil den blå farge vedvarte og ikke noe overskudd av kromsyre var til stede. 50 ml vann ble tilsatt og det vandige lag ble ekstrahert med 4 x 50 ml etylacetat, de organiske lag ble kombinert, ble vasket med 50 ml saltvann, tørket (MgS04), filtrert og konsentrert under dannelse av det ønskede produkt som et hvitt, fast materiale. Data for tittelforbindelsen:<X>H NMR (360 MHz, DMS0) 8 3,41 (2 H, s), 3,43 (2 H, s), 3,73-3,78 (1 H, m), 7,42-7,50 (2 H, m), 7,64-7,72 (1 H, 8 N chromic acid was added to a solution of 3-(2-fluorophenyl)-7-(3-hydroxycyclobutyl)-1,2,4-triazolo[4,3-b]-pyridazin-6-one (0.36 g , 1.2 mmol) in 50 ml acetone, dropwise until excess was present (red color persisted). The reaction mixture was then stirred for 2 h before isopropanol was added until the blue color persisted and no excess chromic acid was present. 50 mL water was added and the aqueous layer was extracted with 4 x 50 mL ethyl acetate, the organic layers were combined, washed with 50 mL brine, dried (MgSO 4 ), filtered and concentrated to give the desired product as a white solid material. Data for the title compound: <X>H NMR (360 MHz, DMSO) δ 3.41 (2 H, s), 3.43 (2 H, s), 3.73-3.78 (1 H, m), 7.42-7.50 (2 H, m), 7.64-7.72 (1 H,

m), 7,83-7,88 (1 H, m), 8,38 (1 H, s); m), 7.83-7.88 (1H, m), 8.38 (1H, s);

MS (ES<*>) m/e 299 [MH]<*>. MS (ES<*>) m/e 299 [MH]<*>.

e) 3-( 2- fluorfenyl)-6-( 2- metyl- 2H- l, 2, 4- triazol- 3- yl-metoksy)- 7-( 3- oksosyklobutyl)- 1 f2 f4- triazolo[ 4, 3- b]-pyridazin e) 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-yl-methoxy)-7-(3-oxocyclobutyl)-1f2f4-triazolo[4, 3-b]-pyridazine

Natriumhydrid (60 % dispersjon i olje, 62 mg, Sodium hydride (60% dispersion in oil, 62 mg,

1,54 mmol) ble tilsatt til en omrørt løsning av 3-(2-fluorfenyl )-7-(3-oksosyklobutyl)-l,2,4-triazolo[4,3-b]pyridazin-6-on (0,23 g, 0,7 mmol) i 5 ml vannfri N,N-dimetylformamid og ble oppvarmet til 80 °C under en nitrogenatmosfære i 0,5 t. Løsningen fikk avkjøles før tilsetning av 5-klormetyl-l-metyl-1H-1,2,4-triazol-monohydroklorid (fremstilt under anvendelse av betingelsene beskrevet i EP-A-170073) (0,14 g, 0,85 mmol). Reaksjonsblandingen ble deretter oppvarmet til 80 °C under en nitrogenatmosfære i 18 t. Løsningen fikk avkjøles, ble konsentrert og residuet ble renset ved kromatografi på silika under anvendelse av 0-5 % metanol/diklormetan som elueringsmiddel, under dannelse av det ønskede produkt som et hvitt, fast materiale. Data for tittelforbindelsen:<l>H NMR (360 MHz, CDC13) 8 3,29-3,38 (2 H, m), 3,45-3,56 (2 H, m), 3,73-3,82 (4 H, m), 5,52 (2 H, s), 7,26-7,31 1.54 mmol) was added to a stirred solution of 3-(2-fluorophenyl)-7-(3-oxocyclobutyl)-1,2,4-triazolo[4,3-b]pyridazin-6-one (0, 23 g, 0.7 mmol) in 5 ml of anhydrous N,N-dimethylformamide and was heated to 80 °C under a nitrogen atmosphere for 0.5 h. The solution was allowed to cool before the addition of 5-chloromethyl-1-methyl-1H-1 ,2,4-triazole monohydrochloride (prepared using the conditions described in EP-A-170073) (0.14 g, 0.85 mmol). The reaction mixture was then heated to 80 °C under a nitrogen atmosphere for 18 h. The solution was allowed to cool, concentrated and the residue was purified by chromatography on silica using 0-5% methanol/dichloromethane as eluent to give the desired product as a white, solid material. Data for the title compound: <1>H NMR (360 MHz, CDCl 3 ) δ 3.29-3.38 (2 H, m), 3.45-3.56 (2 H, m), 3.73-3, 82 (4 H, m), 5.52 (2 H, s), 7.26-7.31

(1 H, m), 7,35-7,39 (1 H, m), 7,56-7,60 (1 H, m), 7,81-7,85 (1 H, m), 7.35-7.39 (1 H, m), 7.56-7.60 (1 H, m), 7.81-7.85

(1 H, m), 7,88 (1 H, s), 7,98 (1 H, s); (1H, m), 7.88 (1H, s), 7.98 (1H, s);

MS (ES<+>) m/e 394 [MH]\ MS (ES<+>) m/e 394 [MH]\

Eksempel 42 Example 42

7-( 3, 3- difluorsyklobutyl)- 3-( 2- fluorfenyl)-6-( 2- metyl- 2H-1, 2, 4- trlazol- 3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 7-( 3, 3- difluorocyclobutyl)- 3-( 2- fluorophenyl)-6-( 2- methyl- 2H-1, 2, 4- trilazol- 3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

En løsning av dietylaminosvoveltrifluorid (0,074 ml, 0,56 mmol) i 6 ml vannfri diklormetan under nitrogen ved -78 °C ble tilsatt til en løsning av 3-(2-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-7-(3-oksosyklobutyl)-1,2,4-triazolo[4,3-b]pyridazin (0,1 g, 0,254 mmol) i 14 ml vannfri diklormetan under nitrogen ved -78 °C. Reaksjonsblandingen fikk oppvarmes til romtemperatur langsomt og ble omrørt i 4 dager. Reaksjonen var ikke fullført; således ble ytterligere 0,037 ml dietylaminosvoveltrifluorid (0,28 mmol) tilsatt ved -78 °C. Etter ytterligere to dager ved romtemperatur var det fremdeles utgangsmateriale tilbake; slik at ytterligere 0,074 ml dietylaminosvoveltrifluorid (0,56 mmol) ble tilsatt ved -78 °C. Totalt ble således 5,5 ekvivalenter dietylaminosvoveltrifluo rid tilsatt over en 10-dagers periode. Løsningen ble tilsatt til 25 ml mettet natriumbikarbonat og is, ble separert, og det vandige lag ble ekstrahert med 2 x 25 ml diklormetan, de organiske lag ble kombinert, ble vasket med 25 ml saltvann, ble tørket (MgS04), filtrert og fordampet. Residuet ble renset ved kromatografi på silikagel og eluering med 0 %—>5 % metanol/diklormetan og ble omkrystallisert fra etylacetat/isoheksan under dannelse av tittelforbindelsen som et blekt orangefarget, A solution of diethylaminosulfur trifluoride (0.074 mL, 0.56 mmol) in 6 mL of anhydrous dichloromethane under nitrogen at -78 °C was added to a solution of 3-(2-fluorophenyl)-6-(2-methyl-2H-1, 2,4-triazol-3-ylmethoxy)-7-(3-oxocyclobutyl)-1,2,4-triazolo[4,3-b]pyridazine (0.1 g, 0.254 mmol) in 14 mL anhydrous dichloromethane under nitrogen at -78 °C. The reaction mixture was allowed to warm to room temperature slowly and was stirred for 4 days. The reaction was not complete; thus, an additional 0.037 mL of diethylaminosulfur trifluoride (0.28 mmol) was added at -78 °C. After two more days at room temperature, starting material still remained; so that an additional 0.074 mL of diethylaminosulfur trifluoride (0.56 mmol) was added at -78 °C. A total of 5.5 equivalents of diethylaminosulfur trifluoride was thus added over a 10-day period. The solution was added to 25 mL of saturated sodium bicarbonate and ice, was separated, and the aqueous layer was extracted with 2 x 25 mL of dichloromethane, the organic layers were combined, washed with 25 mL of brine, dried (MgSO 4 ), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 0%->5% methanol/dichloromethane and was recrystallized from ethyl acetate/isohexane to give the title compound as a pale orange,

fast materiale. Data for tittelforbindelsen: solid material. Data for the title compound:

Smp.: 178 °C; M.p.: 178 °C;

<l>H NMR (400 MHz, CDC13) 6 2,70-2,78 (2 H, m), 3,00-3,07 (2 H, m), 3,47-3,50 (1 H, m), 3,80 (3 H, s), 5,50 (2 H, s), 7,25-7,30 (1 H, m), 7,34-7,38 (1 H, m), 7,56-7,59 (1 H, m), 7,80-7,85 (1 H, m), 7,89 (1 H, s), 7,90 (1 H, s); <1>H NMR (400 MHz, CDCl 3 ) δ 2.70-2.78 (2 H, m), 3.00-3.07 (2 H, m), 3.47-3.50 (1 H , m), 3.80 (3 H, s), 5.50 (2 H, s), 7.25-7.30 (1 H, m), 7.34-7.38 (1 H, m ), 7.56-7.59 (1H, m), 7.80-7.85 (1H, m), 7.89 (1H, s), 7.90 (1H, s);

MS (ES<*>) m/e 416 [MH]<+>; MS (ES<*>) m/e 416 [MH]<+>;

Analyse funnet: C 55,55, H 3,99, N 23,37 % Analysis found: C 55.55, H 3.99, N 23.37%

Ci9H16F3N70 kreves: C 54,94, H 3,88, N 23,60 %. Ci9H16F3N70 required: C 54.94, H 3.88, N 23.60%.

Eksempel 43 Example 43

3- ( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol- 3- ylmetoksy)-7-( tetrahydrofur- 2- yl)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 3-( 2- fluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol- 3- ylmethoxy)-7-( tetrahydrofur- 2- yl)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

Denne forbindelse ble fremstilt under anvendelse av prosedyrene beskrevet i eksempel 1, trinn a), b) og c), under anvendelse av tetrahydro-2-furosyre i stedet for syklobutankarboksylsyre i trinn a). Data for tittelforbindelsen: Smp.: 136-139 °C; This compound was prepared using the procedures described in Example 1, steps a), b) and c), using tetrahydro-2-furoic acid instead of cyclobutanecarboxylic acid in step a). Data for the title compound: mp: 136-139 °C;

<X>H NMR (360 MHz, CDC13) 8 1,77 (1 H, m), 1,98 (2 H, m), 2,42 (1 H, m), 3,82 (3 H, s), 3,98 (1 H, q, J= 7,1 & <X>H NMR (360 MHz, CDCl 3 ) δ 1.77 (1 H, m), 1.98 (2 H, m), 2.42 (1 H, m), 3.82 (3 H, s ), 3.98 (1 H, q, J= 7.1 &

15,4 Hz), 4,15 (1 H, m), 5,01 (1 H, t, J = 6,3 Hz), 5,51 (2 H, q, J = 13,1 & 22,0 Hz), 7,25-7,38 (2 H, m) 7,55 (1 H, m), 7,85 (1 H, m), 7,89 (1 H, s), 8,18 (1 H, s); 15.4 Hz), 4.15 (1 H, m), 5.01 (1 H, t, J = 6.3 Hz), 5.51 (2 H, q, J = 13.1 & 22, 0 Hz), 7.25-7.38 (2 H, m) 7.55 (1 H, m), 7.85 (1 H, m), 7.89 (1 H, s), 8.18 (1H, s);

MS (ES<*>) m/e 396 [MH]<*>. MS (ES<*>) m/e 396 [MH]<*>.

Eksempel 44 Example 44

7-( 3- fluorfenyl)- 3-( 2- fluorfenyl)- 6-( 2- metyl- 2H- l, 2, 4- triazol-3- ylmetoksy)- l, 2, 4- triazolo[ 4, 3- b] pyridazin 7-( 3- fluorophenyl)- 3-( 2- fluorophenyl)- 6-( 2- methyl- 2H- 1, 2, 4- triazol-3- ylmethoxy)- 1, 2, 4- triazolo[ 4, 3- b] pyridazine

En omrørt blanding av 7-brom-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]-pyridazin (50,2 mg, 0,124 mmol), 3-fluorbenzenborsyre A stirred mixture of 7-bromo-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3- b]-pyridazine (50.2 mg, 0.124 mmol), 3-fluorobenzeneboronic acid

(24,7 mg, 0,177 mmol), kaliumfosfat (74,1 mg, 0,339 mmol) og tetrakis(trifenylfosfin)palladium(O) (11,5 mg, 0,00995 mmol) i 3 ml vannfri DMF ble avgasset ved fordampning og kolben ble fylt på nytt med nitrogen 4 ganger, ble deretter oppvarmet til 100 °C under nitrogen i 14,5 t. Blandingen ble fordelt mellom 20 ml etylacetat og 15 ml saltvann. Det vandige lag ble ytterligere ekstrahert med 2 x 20 ml etylacetat og de kombinerte organiske ekstrakter ble fordampet i vakuum. Residuet ble renset ved flashkromatografi (silikagel, 2 % Me0H/CH2Cl2) under dannelse av 18,1 mg (35 %) av tittelforbindelsen som et hvitt, fast materiale: Smp.: 204-206 °C (CH2Cla-Et0Ac-heksan); (24.7 mg, 0.177 mmol), potassium phosphate (74.1 mg, 0.339 mmol) and tetrakis(triphenylphosphine)palladium(O) (11.5 mg, 0.00995 mmol) in 3 mL anhydrous DMF were degassed by evaporation and the flask was refilled with nitrogen 4 times, then heated to 100°C under nitrogen for 14.5 h. The mixture was partitioned between 20 mL ethyl acetate and 15 mL brine. The aqueous layer was further extracted with 2 x 20 ml of ethyl acetate and the combined organic extracts were evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 2% Me0H/CH2Cl2) to give 18.1 mg (35%) of the title compound as a white solid: mp: 204-206 °C (CH2Cla-Et0Ac-hexane);

<X>H NMR (360 MHz, CDC13) 5 3,70 (3 H, s), 5,54 (2 H, s), 7,18 (1 H, m), 7,28-7,40 (4 H, m), 7,46 (1 H, m), 7,58 <X>H NMR (360 MHz, CDCl 3 ) δ 3.70 (3 H, s), 5.54 (2 H, s), 7.18 (1 H, m), 7.28-7.40 ( 4 H, m), 7.46 (1 H, m), 7.58

(1 H, m), 7,86 (1 H, s), 7,88 (1 H, td, J = 7,5 og 1,8 Hz), 8,08 (1 H, s); (1 H, m), 7.86 (1 H, s), 7.88 (1 H, td, J = 7.5 and 1.8 Hz), 8.08 (1 H, s);

MS (ES<*>) m/e 420 [MH]\ MS (ES<*>) m/e 420 [MH]\

Claims (14)

1. Forbindelse, karakterisert vedformel I, eller et farma-søytisk akseptabelt salt derav: 1. Connection, characterized by formula I, or a pharmaceutically acceptable salt thereof: hvori Z betegner trifluormetyl, 2-metylpropyl, 2,2-dimetyl- propyl, 3-metylbutyl, 1-fluorbut-3-enyl, syklobutyl, 1-metylsyklobutyl, 1-fluorsyklobutyl, 3-fluorsyklobutyl , 3,3-difluorsyklobutyl, 3-hydroksysyklobutyl, 3-benzyloksysyklobutyl, 3-oksosyklobutyl, 1-metylsykloheksyl, 4,4-difluor-1-metylsykloheksyl, syklopentylmetyl, 4-fluorsykloheks-3-enyl, 3-fluorfenyl, tetrahydrofur-2-yl, pyrrolidin-l-yl, 4-metyltetrahydropyran-4-yl eller tien-2-yl, R<1>betegner hydrogen eller fluor, og R<z>betegner metyl-isoksazolyl, metyl-pyrazolyl, metyl- imidazolyl, benzimidazolyl eller metyl-triazolyl, forutsatt at når Z betegner 1-metylsyklobutyl. R<1>er hydrogen og R<2>betegner 1-metyl-lH-l,2,4-triazol-3-yl eller 2-metyl-2H-1,2,4-triazol-3-yl, er fluoratomet ikke ved 2-stillingen av fenylringen.in which Z denotes trifluoromethyl, 2-methylpropyl, 2,2-dimethyl- propyl, 3-methylbutyl, 1-fluorobut-3-enyl, cyclobutyl, 1-methylcyclobutyl, 1-fluorocyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 3-hydroxycyclobutyl, 3-benzyloxycyclobutyl, 3-oxocyclobutyl, 1-methylcyclohexyl, 4,4-difluoro-1-methylcyclohexyl, cyclopentylmethyl, 4-fluorocyclohex-3-enyl, 3-fluorophenyl, tetrahydrofur-2-yl, pyrrolidin-1-yl, 4-methyltetrahydropyran-4-yl or thien-2-yl, R<1> denotes hydrogen or fluorine, and R<z>denotes methyl-isoxazolyl, methyl-pyrazolyl, methyl- imidazolyl, benzimidazolyl or methyltriazolyl, provided that when Z represents 1-methylcyclobutyl. R<1> is hydrogen and R<2> denotes 1-methyl-1H-1,2,4-triazol-3-yl or 2-methyl-2H-1,2,4-triazol-3-yl, is the fluorine atom not at the 2-position of the phenyl ring. 2. Forbindelse ifølge krav 1,karakterisert vedatZ betegner syklobutyl.2. Compound according to claim 1, characterized in that Z denotes cyclobutyl. 3. Forbindelse ifølge krav 1 eller 2,karakterisert vedat R! betegner en ring av struktur (a), (b), (c), (d), (e), (f) eller (g): 3. Compound according to claim 1 or 2, characterized in that R! denotes a ring of structure (a), (b), (c), (d), (e), (f) or (g): hvori stjernen angir bindingspunktet av ringen til resten av molekylet.in which the asterisk indicates the point of attachment of the ring to the rest of the molecule. 4. Forbindelse ifølge krav 3,karakterisert vedat R<2>betegner en ring av struktur (g) som vist i krav 3.4. Compound according to claim 3, characterized in that R<2> denotes a ring of structure (g) as shown in claim 3. 5. Forbindelse Ifølge krav 1,karakterisert vedformel IIA og farmasøytisk akseptable salter derav: 5. Compound according to claim 1, characterized by formula IIA and pharmaceutically acceptable salts thereof: hvori R<1>er som definert i krav 1; ogR<3>betegner hydrogen eller fluor.in which R<1> is as defined in claim 1; and R<3> denotes hydrogen or fluorine. 6. Forbindelse ifølge krav 5,karakterisert vedat den er representert ved formel UB, og farmasøytisk akseptable salter derav: 6. Compound according to claim 5, characterized in that it is represented by formula UB, and pharmaceutically acceptable salts thereof: hvori R<1>er som definert i krav 1, og R<3>er som definert i krav 5.in which R<1> is as defined in claim 1, and R<3> is as defined in claim 5. 7. Forbindelse ifølge krav 5 eller 6,karakterisert vedat R<3>betegner hydrogen.7. Compound according to claim 5 or 6, characterized in that R<3> denotes hydrogen. 8. Forbindelse, karakterisert vedat den er valgt fra: 7-syklobutyl-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-syklobutyl-3-(2-fluorfenyl)-6-(1-metyl-lH-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-syklobutyl-3-(3-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-syklobutyl-3-(4-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-syklobutyl-3-(2,4-difluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-syklobutyl-3-(3,5-difluorfenyl)-6- (2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 3-(2,4-difluorfenyl)-7-(1-metylsyklobutyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]-pyridazin, 7-syklobutyl-3-(3,4-difluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-syklobutyl-3-(2,3-difluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-syklobutyl-3-{2,6-difluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-syklobutyl-3-(2,5-di fluorfenyl)-6-(2-metyl- 2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 3-(2,4-difluorfenyl)-7-(1-metylsykloheksyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]-pyridazin, 3-(2,4-difluorfenyl)-7-(1-metylsykloheksyl)-6-(1-metyl-lH-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]-pyridazin, 7-syklobutyl-3-(2-fluorfenyl)-6-(1-metyl-lH-pyrazol-3- ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-syklobutyl-3-(2-fluorfenyl)-6-(5-metylisoksazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-syklobutyl-3-(2-fluorfenyl)-6-(1-metyl-lH-imidazol-2- ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-syklobutyl-3-(2-fluorfenyl)-6-(4-metyl-4H-l,2,4-trlazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-yl-metoksy)-7-(tlen-2-yl)-1,2,4-triazolo[4,3-b]pyridazin, 3-(2,4-difluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-7-(tien-2-yl)-1,2,4-triazolo[4,3-b]pyridazin, 6- (lH-benzimidazol-2-ylmetoksy)-7-syklobutyl-3-(2,4-difluorfenyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-(2,4-difluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-yImetoksy)-7-{pyrrolidin-l-yl)-l,2,4-triazolo[4,3-b]pyridazin, 3- (2,4-difluorfenyl)-6-(1-metyl-lH-l,2,4-triazol-3-ylmetoksy)-7-(pyrrolidin-l-yl)-1,2,4-triazolo[4,3-b]pyridazin, 3-(2-fluorfenyl)-6-(1-metyl-lH-l,2,4-triazol-3-yl-metoksy)-7-(pyrrolidin-l-yl)-1,2,4-triazolo[4,3-b]pyridazin, 7- syklobutyl-3-(2-fluorfenyl)-6-(1-metyl-lH-imidazol-8. Connection, characterized in that it is selected from: 7-cyclobutyl-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4 ,3-b]pyridazine, 7-cyclobutyl-3-(2-fluorophenyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4 ,3-b]pyridazine, 7-cyclobutyl-3-(3-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4 ,3-b]pyridazine, 7-cyclobutyl-3-(4-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4 ,3-b]pyridazine, 7-cyclobutyl-3-(2,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine, 7-cyclobutyl-3-(3,5-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4 -triazolo[4,3-b]pyridazine, 3-(2,4-difluorophenyl)-7-(1-methylcyclobutyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy) -1,2,4-triazolo[4,3-b]-pyridazine, 7-cyclobutyl-3-(3,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazole-3 -ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine, 7-cyclobutyl-3-(2,3-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazole -3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine, 7-sy chlorobutyl-3-{2,6-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine, 7-cyclobutyl-3-(2,5-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b ]pyridazine, 3-(2,4-difluorophenyl)-7-(1-methylcyclohexyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]-pyridazine, 3-(2,4-difluorophenyl)-7-(1-methylcyclohexyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)- 1,2,4-triazolo[4,3-b]-pyridazine, 7-cyclobutyl-3-(2-fluorophenyl)-6-(1-methyl-1H-pyrazol-3-ylmethoxy)-1,2,4 -triazolo[4,3-b]pyridazine, 7-cyclobutyl-3-(2-fluorophenyl)-6-(5-methylisoxazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine , 7-cyclobutyl-3-(2-fluorophenyl)-6-(1-methyl-1H-imidazol-2-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine, 7-cyclobutyl-3 -(2-Fluorophenyl)-6-(4-methyl-4H-1,2,4-trazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine, 3-(2- fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-yl-methoxy)-7-(tlen-2-yl)-1,2,4-triazolo[4,3-b ]pyridazine, 3-(2,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-y lmethoxy)-7-(thien-2-yl)-1,2,4-triazolo[4,3-b]pyridazine, 6-(1H-benzimidazol-2-ylmethoxy)-7-cyclobutyl-3-(2, 4-difluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine, 3-(2,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3- yImethoxy)-7-{pyrrolidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine, 3-(2,4-difluorophenyl)-6-(1-methyl-1H-1, 2,4-triazol-3-ylmethoxy)-7-(pyrrolidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine, 3-(2-fluorophenyl)-6-(1- methyl-1H-1,2,4-triazol-3-yl-methoxy)-7-(pyrrolidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine, 7-cyclobutyl-3 -(2-fluorophenyl)-6-(1-methyl-1H-imidazole- 4- ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-(1-fluorsyklobutyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-syklobutyl-3-(2-fluorfenyl)-6-(2-metyl-2H-pyrazol-3- ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, og farmasøytisk akseptable salter derav.4-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine, 7-(1-fluorocyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3- b]pyridazine, 7-cyclobutyl-3-(2-fluorophenyl)-6-(2-methyl-2H-pyrazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine, and pharmaceutically acceptable salts thereof. 9. Forbindelse, karakterisert vedat den er valgt fra: 7-(2,2-dimetylpropyl)-3-{2-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 3-(2-fluorfenyl)-7-(2-metylpropyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l/2,4-triazolo[4,3-b]pyridazin, 3-(2-fluorfenyl)-7-(3-metylbutyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, 7-syklopentylmetyl-3-(2-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-(3-benzyloksysyklobutyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-l, 2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 3-(2-fluorfenyl)-7-(3-hydroksysyklobutyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-(1-fluorbut-3-enyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 7-(3-fluorsyklobutyl)-3-{2-fluorfenyl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]pyridazin, 3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-yl-metoksy)-7-trifluormetyl-1,2,4-triazolo[4,3-b]pyridazin, og farmasøytisk akseptable salter derav.9. Connection, characterized in that it is selected from: 7-(2,2-dimethylpropyl)-3-{2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2 ,4-triazolo[4,3-b]pyridazine, 3-(2-fluorophenyl)-7-(2-methylpropyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy) -1/2,4-triazolo[4,3-b]pyridazine, 3-(2-fluorophenyl)-7-(3-methylbutyl)-6-(2-methyl-2H-1,2,4-triazol- 3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine, 7-cyclopentylmethyl-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol- 3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine, 7-(3-benzyloxycyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1, 2, 4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine, 3-(2-fluorophenyl)-7-(3-hydroxycyclobutyl)-6-(2-methyl-2H- 1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine, 7-(1-fluorobut-3-enyl)-3-(2-fluorophenyl)-6 -(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine, 7-(3-fluorocyclobutyl)-3-{2- fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine, 3-(2-fluorophenyl)-6 -(2-methyl-2H-1,2,4-triazol-3-yl-methoxy)-7-trifluoro methyl-1,2,4-triazolo[4,3-b]pyridazine, and pharmaceutically acceptable salts thereof. 10. Forbindelse, karakterisert vedat den er valgt fra: 3-(2-fluorfenyl)-7-(4-metyltetrahydropyran-4-yl)-6-(2-metyl-2H-1,2,4-triazol-3-ylmetoksy)-1,2,4-triazolo[4,3-b]-pyridazin, 3-(2-fluorfenyl)-7-(4-metyltetrahydropyran-4-yl)-6-(1-metyl-1H-1,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]-pyridazin, 7-(4,4-difluor-1-metylsykloheksyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo-[4,3-b]pyridaz in, 7-(4-fluor-1-metylsykloheks-3-enyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo-[4,3-b]pyridazin, 7-(4,4-difluor-l-metylsykloheksyl)-3-(2-fluorfenyl) - 6-(1-metyl-lH-l,2,4-triazol-3-ylmetoksy)-l,2,4-triazolo-[4,3-b]pyridazin, 3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-yl-metoksy)-7-(3-oksosyklobutyl)-1,2,4-triazolo[4,3-b]pyridazin, 7-(3,3-difluorsyklobutyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-ylmetoksy) -1,2,4-triazolo[4,3-b]-pyridazin, 3-(2-fluorfenyl)-6-(2-metyl-2H-l,2,4-triazol-3-yl-metoksy)-7-(tetrahydrofur-2-yl)-1,2,4-triazolo[4,3-b]-pyridazin, 7-(3-fluorfenyl)-3-(2-fluorfenyl)-6-(2-metyl-2H-I, 2,4-triazol-3-ylmetoksy)-l,2,4-triazolo[4,3-b]pyridazin, og farmasøytisk akseptable salter derav. 10. Connection, characterized in that it is selected from: 3-(2-fluorophenyl)-7-(4-methyltetrahydropyran-4-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1 ,2,4-triazolo[4,3-b]-pyridazine, 3-(2-fluorophenyl)-7-(4-methyltetrahydropyran-4-yl)-6-(1-methyl-1H-1,2,4 -triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]-pyridazine, 7-(4,4-difluoro-1-methylcyclohexyl)-3-(2-fluorophenyl)-6-( 2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo-[4,3-b]pyridazine, 7-(4-fluoro-1-methylcyclohex-3- enyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo-[4,3-b]pyridazine, 7-(4,4-difluoro-1-methylcyclohexyl)-3-(2-fluorophenyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-1,2,4- triazolo-[4,3-b]pyridazine, 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-yl-methoxy)-7-(3-oxocyclobutyl) -1,2,4-triazolo[4,3-b]pyridazine, 7-(3,3-difluorocyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4- triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]-pyridazine, 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3 -yl-methoxy)-7-(tetrahydrofur-2-yl)-1,2,4-triazolo[4,3-b]- pyridazine, 7-(3-fluorophenyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4, 3-b]pyridazine, and pharmaceutically acceptable salts thereof. II. Farmasøytisk preparat, karakterisert vedat det omfatter en forbindelse av formel X som definert i krav 1, eller et farmasøytisk akseptabelt salt derav, i assosiasjon med en farmasøytisk akseptabel bærer.II. Pharmaceutical preparation, characterized in that it comprises a compound of formula X as defined in claim 1, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier. 12. Anvendelse av en forbindelse ifølge hvilket som helst av kravene 1 til 10, for fremstilling av et medikament for behandling og/eller forhindring av angst.12. Use of a compound according to any one of claims 1 to 10, for the production of a drug for the treatment and/or prevention of anxiety. 13. Anvendelse av en forbindelse ifølge hvilket som helst av kravene 1 til 10, for fremstilling av et medikament for behandling og/eller forhindring av konvulsjoner.13. Use of a compound according to any one of claims 1 to 10, for the preparation of a medicament for the treatment and/or prevention of convulsions. 14. Fremgangsmåte for fremstilling av en forbindelse ifølge krav 1,karakterisert vedat den omfatter: (A) omsetning av en forbindelse av formel III med en forbindelse av formel IV: 14. Process for producing a compound according to claim 1, characterized in that it comprises: (A) reacting a compound of formula III with a compound of formula IV: hvori Z, R<1>og R3 er som definert i krav 1, og L<1>betegner en egnet, forlatende gruppe; eller (B) omsetning av en forbindelse av formel XI (eller dens 1,2,4-triazolo[4,3-b]pyridazin-6-on-tautomer) med en forbindelse av formel XII: wherein Z, R<1> and R3 are as defined in claim 1, and L<1> denotes a suitable leaving group; or (B) reacting a compound of formula XI (or its 1,2,4-triazolo[4,3-b]pyridazin-6-one tautomer) with a compound of formula XII: hvori Z,R<1>ogR<2>er som definert i krav 1, og L<3>betegner en egnet forlatende gruppe; eller (C) omsetning av en forbindelse av formel Z-C02H med en forbindelse av formel XIII: wherein Z, R<1> and R<2> are as defined in claim 1, and L<3> denotes a suitable leaving group; or (C) reacting a compound of formula Z-CO 2 H with a compound of formula XIII: hvori Z, R<1>og R<2>er som definert i krav 1; i nærvær av sølv-nitrat og ammoniumpersulfat; eller (D) omsetning av en forbindelse av formel XIV med en forbindelse av formel XV: wherein Z, R<1> and R<2> are as defined in claim 1; in the presence of silver nitrate and ammonium persulfate; or (D) reacting a compound of formula XIV with a compound of formula XV: hvori Z, R<1>og R<2>er som definert i krav 1, M betegner -B(OH)2eller -Sn(Alk)3, hvori Alk betegner en Cx_6-alkylgruppe, og L<4>betegner en egnet forlatende gruppe; i nærvær av en overgangsmetallkatalysator; eller (E) omsetning av en forbindelse av formel XVII: wherein Z, R<1> and R<2> are as defined in claim 1, M denotes -B(OH)2 or -Sn(Alk)3, wherein Alk denotes a Cx_6 alkyl group, and L<4> denotes a suitable leaving group; in the presence of a transition metal catalyst; or (E) conversion of a compound of formula XVII: hvoriR<1>og R<2>er som definert i krav 1; med et fluorerings-raiddel; eller (F) omsetning av en forbindelse av formel XVIII: wherein R<1> and R<2> are as defined in claim 1; with a fluorination raid part; or (F) converting a compound of formula XVIII: hvoriR<1>og R<2>er som definert i krav 1; med et fluoreringsmiddel; eller (G) omsetning av en forbindelse av formel I hvori Z betegner 3-oksosyklobutyl, med et fluoreringsmiddel; eller (H) hydrogenolyse av en forbindelse av formel XXI: wherein R<1> and R<2> are as defined in claim 1; with a fluorinating agent; or (G) reacting a compound of formula I wherein Z represents 3-oxocyclobutyl, with a fluorinating agent; or (H) hydrogenolysis of a compound of formula XXI: hvori R<1>og R<2>er som definert i krav 1; eller (I) omsetning av en forbindelse av formel XXII med en forbindelse av formel XXIII: wherein R<1> and R<2> are as defined in claim 1; or (I) reacting a compound of formula XXII with a compound of formula XXIII: hvori Z,R<1>ogR<2>er som definert i krav 1, L<5>betegner en egnet forlatende gruppe og E betegner -B(OH)2eller resten av et organosinkreagens; i nærvar av en overgangsmetallkatalysator; eller (J) omsetning av en forbindelse av formel XXII som ovenfor definert, med jodtrifluormetan.wherein Z, R<1> and R<2> are as defined in claim 1, L<5> denotes a suitable leaving group and E denotes -B(OH) 2 or the residue of an organozinc reagent; in the presence of a transition metal catalyst; or (J) reacting a compound of formula XXII as defined above with iodotrifluoromethane.